"Periodic crises": Clément Juglar between theories of crises and theories of business cycles

Business cycle theory is normally described as having evolved out of a previous tradition of writers focusing exclusively on crises. In this account, the turning point is seen as residing in Clément Juglar's contribution on commercial crises and their periodicity. It is well known that the champion of this view is Schumpeter, who propagated it on several occasions. The same author, however, pointed to a number of other writers who, before and at the same time as Juglar, stressed one or another of the aspects for which Juglar is credited primacy, including the recognition of periodicity and the identification of endogenous elements enabling the recognition of crises as a self-generating phenomenon. There is indeed a vast literature, both primary and secondary, relating to the debates on crises and fluctuations around the middle of the nineteenth century, from which it is apparent that Juglar's book Des Crises Commerciales et de leur Retour Périodique en France, en Angleterre et aux États-Unis (originally published in 1862 and very much revised and enlarged in 1889) did not come out of the blue but was one of the products of an intellectual climate inducing the thinking of crises not as unrelated events but as part of a more complex phenomenon consisting of recurring crises related to the development of the commercial world - an interpretation corroborated by the almost regular occurrence of crises at about 10-year intervals.

Individual contributions of mutant protease and reverse transcriptase to viral infectivity, replication, and protein maturation of antiretroviral drug-resistant human immunodeficiency virus type 1.

Human immunodeficiency virus type 1 (HIV-1) variants resistant to protease (PR) and reverse transcriptase (RT) inhibitors may display impaired infectivity and replication capacity. The individual contributions of mutated HIV-1 PR and RT to infectivity, replication, RT activity, and protein maturation (herein referred to as "fitness") in recombinant viruses were investigated by separately cloning PR, RT, and PR-RT cassettes from drug-resistant mutant viral isolates into the wild-type NL4-3 background. Both mutant PR and RT contributed to measurable deficits in fitness of viral constructs. In peripheral blood mononuclear cells, replication rates (means +/- standard deviations) of RT recombinants were 72.5% +/- 27.3% and replication rates of PR recombinants were 60.5% +/- 33.6% of the rates of NL4-3. PR mutant deficits were enhanced in CEM T cells, with relative replication rates of PR recombinants decreasing to 15.8% +/- 23.5% of NL4-3 replication rates. Cloning of the cognate RT improved fitness of some PR mutant clones. For a multidrug-resistant virus transmitted through sexual contact, RT constructs displayed a marked infectivity and replication deficit and diminished packaging of Pol proteins (RT content in virions diminished by 56.3% +/- 10.7%, and integrase content diminished by 23.3% +/- 18.4%), a novel mechanism for a decreased-fitness phenotype. Despite the identified impairment of recombinant clones, fitness of two of the three drug-resistant isolates was comparable to that of wild-type, susceptible viruses, suggestive of extensive compensation by genomic regions away from PR and RT. Only limited reversion of mutated positions to wild-type amino acids was observed for the native isolates over 100 viral replication cycles in the absence of drug selective pressure. These data underscore the complex relationship between PR and RT adaptive changes and viral evolution in antiretroviral drug-resistant HIV-1.

TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1-TRAF2 complex to sensitize tumor cells to TNFalpha.

Synthetic inhibitor of apoptosis (IAP) antagonists induce degradation of IAP proteins such as cellular IAP1 (cIAP1), activate nuclear factor kappaB (NF-kappaB) signaling, and sensitize cells to tumor necrosis factor alpha (TNFalpha). The physiological relevance of these discoveries to cIAP1 function remains undetermined. We show that upon ligand binding, the TNF superfamily receptor FN14 recruits a cIAP1-Tnf receptor-associated factor 2 (TRAF2) complex. Unlike IAP antagonists that cause rapid proteasomal degradation of cIAP1, signaling by FN14 promotes the lysosomal degradation of cIAP1-TRAF2 in a cIAP1-dependent manner. TNF-like weak inducer of apoptosis (TWEAK)/FN14 signaling nevertheless promotes the same noncanonical NF-kappaB signaling elicited by IAP antagonists and, in sensitive cells, the same autocrine TNFalpha-induced death occurs. TWEAK-induced loss of the cIAP1-TRAF2 complex sensitizes immortalized and minimally passaged tumor cells to TNFalpha-induced death, whereas primary cells remain resistant. Conversely, cIAP1-TRAF2 complex overexpression limits FN14 signaling and protects tumor cells from TWEAK-induced TNFalpha sensitization. Lysosomal degradation of cIAP1-TRAF2 by TWEAK/FN14 therefore critically alters the balance of life/death signals emanating from TNF-R1 in immortalized cells.

Validation of two echocardiographic indexes to improve the diagnosis of complex coarctations

Rapport de synthèse: Enjeux et contexte de recherche : la coarctation de l'aorte, rétrécissement de l'aorte thoracique descendante, est une des malformations cardiaques congénitales les plus fréquentes. Son diagnostic reste cependant difficile surtout lorsqu'elle est associée à la présence d'un canal artériel ou à une malformation cardiaque plus complexe. Dans ces contextes, les signes échographiques classiques qui posent habituellement le diagnostic (visualisation d'un rétrécissement juxtaductal et accélération au Doppler au niveau de l'isthme aortique) peuvent faire défaut ou être difficile à imager. La validation d'index basé sur des mesures anatomiques faciles à acquérir par échographie cardiaque, indépendantes de l'âge, de la situation hémodynamique et des malformations cardiaques associées représente une aide significative dans le diagnostic de la coarctation de l'aorte. Nous avons donc voulu valider par une étude rétrospective la fiabilité de deux index dans cette indication : l'index des artères carotido-sous-clavière (index CSA; rapport du diamètre de l'arc aortique transverse distal sur la distance entre les artères carotide et sous-clavière gauches) et l'index de l'aorte isthmique-descendante (index I/D; rapport des diamètres de l'aorte isthmique sur celui de l'aorte descendante). Notre article : nous avons rétrospectivement calculé la valeur des deux index (CSA et I/D) chez un groupe de 68 enfants avec coarctation et un groupe 24 cas contrôles apparenté pour l'âge et le sexe. Les enfants avec coarctation ont un index CSA et I/D significativement plus bas que le groupe contrôle (Index CSA : 0.84 ± 0.39 vs. 2.65 ± 0.82, p<0.0001 - Index I/D : 0.58 ± 0.18 vs. 0.98 ± 0.19, p<0.0001). Pour les deux index, ni la présence d'une autre malformation cardiaque, ni l'âge n'ont un impact sur la différence significative entre les deux groupes. Conclusions: notre recherche à permis de valider qu'un index CSA de moins de 1,5 est fortement suggestif d'une coarctation, indépendamment de l'âge du patient et de la présence d'une autre malformation cardiaque. L'index I/D (valeur limite 0,64) est moins spécifique que l'index CSA. L'association des deux index augmente la sensibilité et permet rétrospectivement le diagnostic de tous les cas de coarctation seulement sur la base d'une échographie cardiaque standard faite au lit du patient. Perspectives : cette étude rétrospective mérite d'être vérifiée par une étude prospective afin de confirmer la contribution de ces index à la prise en charge des patients suspects d'une coarctation de l'aorte. Cependant, la situation dans laquelle ces index pourraient avoir le plus grand impact reste encore à explorer. En effet, si le diagnostic postnatal de la coarctation est parfois difficile, son diagnostic prénatal l'est nettement plus. La présence obligatoire du canal artériel et l'existence d'une hypoplasie isthmique physiologique chez le foetus obligent le cardiologue foetale à observer des signes indirects, peu sensibles, d'une possible coarctation (prépondérance des cavités droites). La validation de l'index CSA et/ou de l'index I/D chez le foetus constituerait donc une avancée majeure dans le diagnostic prénatal de la coarctation de l'aorte.

Selective abrogation of major histocompatibility complex class II expression on extrahematopoietic cells in mice lacking promoter IV of the class II transactivator gene.

MHC class II (MHCII) molecules play a pivotal role in the induction and regulation of immune responses. The transcriptional coactivator class II transactivator (CIITA) controls MHCII expression. The CIITA gene is regulated by three independent promoters (pI, pIII, pIV). We have generated pIV knockout mice. These mice exhibit selective abrogation of interferon (IFN)-gamma-induced MHCII expression on a wide variety of non-bone marrow-derived cells, including endothelia, epithelia, astrocytes, and fibroblasts. Constitutive MHCII expression on cortical thymic epithelial cells, and thus positive selection of CD4(+) T cells, is also abolished. In contrast, constitutive and inducible MHCII expression is unaffected on professional antigen-presenting cells, including B cells, dendritic cells, and IFN-gamma-activated cells of the macrophage lineage. pIV(-/-) mice have thus allowed precise definition of CIITA pIV usage in vivo. Moreover, they represent a unique animal model for studying the significance and contribution of MHCII-mediated antigen presentation by nonprofessional antigen-presenting cells in health and disease.

Analysis of Mycobacterium avium Complex Serovars Isolated from AIDS Patients from Southeast Brazil

The purpose of this study was to assess the distribution of Mycobacterium avium serovars isolated from AIDS patients in São Paulo and Rio de Janeiro. Ninety single site or multiple site isolates from 75 patients were examined. The most frequent serovars found were 8 (39.2%), 4 (21.4%) and 1 (10.7%). The frequency of mixed infections with serovar 8 or 4 was 37.8%. Among the 90 strains examined, M. intracellulare serovars (7 strains) and M. scrofulaceum (4 strains) were found in 11 isolates (12%) indicating that M. avium (88%) was the major opportunistic species in the M. avium complex isolates in Brazilian AIDS patients

Dihydroaeruginoic acid synthetase and pyochelin synthetase, products of the pchEF genes, are induced by extracellular pyochelin in Pseudomonas aeruginosa.

The siderophore pyochelin of Pseudomonas aeruginosa is derived from one molecule of salicylate and two molecules of cysteine. Two cotranscribed genes, pchEF, encoding peptide synthetases have been identified and characterized. pchE was required for the conversion of salicylate to dihydroaeruginoate (Dha), the condensation product of salicylate and one cysteine residue and pchF was essential for the synthesis of pyochelin from Dha. The deduced PchE (156 kDa) and PchF (197 kDa) proteins had adenylation, thiolation and condensation/cyclization motifs arranged as modules which are typical of those peptide synthetases forming thiazoline rings. The pchEF genes were coregulated with the pchDCBA operon, which provides enzymes for the synthesis (PchBA) and activation (PchD) of salicylate as well as a putative thioesterase (PchC). Expression of a translational pchE'-'lacZ fusion was strictly dependent on the PchR regulator and was induced by extracellular pyochelin, the end product of the pathway. Iron replete conditions led to Fur (ferric uptake regulator)-dependent repression of the pchE'-'lacZ fusion. A translational pchD'-'lacZ fusion was also positively regulated by PchR and pyochelin and repressed by Fur and iron. Thus, autoinduction by pyochelin (or ferric pyochelin) and repression by iron ensure a sensitive control of the pyochelin pathway in P. aeruginosa.

Investigation of the hepatitis C virus replication complex.

Formation of a membrane-associated replication complex, composed of viral proteins, replicating RNA, altered cellular membranes, and other host factors, is a hallmark of all positive-strand RNA viruses. In the case of HCV, RNA replication takes place in a likely endoplasmic reticulum-derived membrane alteration referred to as the "membranous web." In vitro transcription-translation, membrane extraction and flotation analyses, immunofluorescence microscopy, fluorescent in situ hybridization, and RNA metabolic labeling followed by confocal laser scanning microscopy have yielded insights into the structure and function of the HCV replication complex. We describe these techniques and highlight selected results.

Protein-protein interaction investigated by steered molecular dynamics: the TCR-pMHC complex.

We present a novel steered molecular dynamics scheme to induce the dissociation of large protein-protein complexes. We apply this scheme to study the interaction of a T cell receptor (TCR) with a major histocompatibility complex (MHC) presenting a peptide (p). Two TCR-pMHC complexes are considered, which only differ by the mutation of a single amino acid on the peptide; one is a strong agonist that produces T cell activation in vivo, while the other is an antagonist. We investigate the interaction mechanism from a large number of unbinding trajectories by analyzing van der Waals and electrostatic interactions and by computing energy changes in proteins and solvent. In addition, dissociation potentials of mean force are calculated with the Jarzynski identity, using an averaging method developed for our steering scheme. We analyze the convergence of the Jarzynski exponential average, which is hampered by the large amount of dissipative work involved and the complexity of the system. The resulting dissociation free energies largely underestimate experimental values, but the simulations are able to clearly differentiate between wild-type and mutated TCR-pMHC and give insights into the dissociation mechanism.

The complex history of the olive tree: from Late Quaternary diversification of Mediterranean lineages to primary domestication in the northern Levant.

The location and timing of domestication of the olive tree, a key crop in Early Mediterranean societies, remain hotly debated. Here, we unravel the history of wild olives (oleasters), and then infer the primary origins of the domesticated olive. Phylogeography and Bayesian molecular dating analyses based on plastid genome profiling of 1263 oleasters and 534 cultivated genotypes reveal three main lineages of pre-Quaternary origin. Regional hotspots of plastid diversity, species distribution modelling and macrofossils support the existence of three long-term refugia; namely the Near East (including Cyprus), the Aegean area and the Strait of Gibraltar. These ancestral wild gene pools have provided the essential foundations for cultivated olive breeding. Comparison of the geographical pattern of plastid diversity between wild and cultivated olives indicates the cradle of first domestication in the northern Levant followed by dispersals across the Mediterranean basin in parallel with the expansion of civilizations and human exchanges in this part of the world.

The role of basalt replenishment in the generation of basaltic andesites of the ongoing activity at Arenal volcano, Costa Rica: evidence from clinopyroxene and spinel

The bulk composition of magma erupted from Volcan Arenal has remained nearly constant (SiO2 = 53.6-54.9 wt%; MgO = 5.0-4.5 wt%) during almost 30 years of continuous activity (1969-1996). None the less, clinopyroxene (cpx) phenocrysts and their spinel inclusions record a much more complex open-system evolution in which steady-state production of the erupted basaltic andesitic magma is linked to episodic injections of basalt into Arenal's magma conduit/reservoir system. High-resolution major element zoning profiles (electron microprobe) on a large number of phenocrysts (>14,000 analyses), tied to back-scattered electron (BSE) images, have been used to assess the compositional characteristics of the magmatic end members as well as the timing and dynamics of magma replenishment events. No two cpx phenocrysts have exactly the same zoning profile. The vast majority of our analyses record the crystallization of cpx (Cr2O3 < 0.12 wt%; Mg# = 65-79; Al/Ti = 2-7) from a liquid comparable to or more evolved than erupted magma compositions. However, half of all cpx grains are cored by high-Cr cpx (Cr2O3 = 0.2-0.72 wt%) or contain similar basaltic compositions as abrupt growth bands in phenocrysts with and without high-Cr cores; phenocrysts with high-Cr cpx occur throughout the ongoing activity. In a few cases, high-Cr cpx occurs very near the outer margin of the grain without an apparent growth hiatus, particularly in 1968/69 and 1992/93. The main conclusions are: (1) all basaltic andesitic lavas erupted at Arenal during the ongoing activity that began in July, 1968, are the products of magma mixing, (2) clinopyroxenes record multiple replenishment events of basaltic magma in contrast to the near constancy of erupted bulk compositions, (3) some phenocrysts preserve records of multiple interactions with basaltic magmas requiring magmatic processes to operate on time-scales shorter than residence times of some phenocrysts, (4) multiple occurrences of clinopyroxene with high-Cr rims suggest that basalt replenishment events have occurred with sub-decadal frequency and may predate eruption by months or less. From this we infer that Arenal volcano is underlain by a continuously active, small-volume magmatic reservoir maintained in quasi-steady state by basalt recharge over several decades. The monotony of erupting Arenal magmas implies that fractionation, recharge, ascent, and eruption are well balanced in order for magmas to be essentially uniform while containing phenocrysts with vastly different growth histories at the time of eruption.

On finite unions and finite products with the D-property

We show that the product of a subparacompact C-scattered space and a Lindelöf D-space is D. In addition, we show that every regular locally D-space which is the union of a finite collection of subparacompact spaces and metacompact spaces has the D-property. Also, we extend this result from the class of locally D-spaces to the wider class of D-scattered spaces. All the results are shown in a direct way.

Study of Staphylococcus aureus pathogenic genes by transfer and expression in the less virulent organism Streptococcus gordonii.

Because Staphylococcus aureus strains contain multiple virulence factors, studying their pathogenic role by single-gene inactivation generated equivocal results. To circumvent this problem, we have expressed specific S. aureus genes in the less virulent organism Streptococcus gordonii and tested the recombinants for a gain of function both in vitro and in vivo. Clumping factor A (ClfA) and coagulase were investigated. Both gene products were expressed functionally and with similar kinetics during growth by streptococci and staphylococci. ClfA-positive S. gordonii was more adherent to platelet-fibrin clots mimicking cardiac vegetations in vitro and more infective in rats with experimental endocarditis (P &lt; 0.05). Moreover, deleting clfA from clfA-positive streptococcal transformants restored both the low in vitro adherence and the low in vivo infectivity of the parent. Coagulase-positive transformants, on the other hand, were neither more adherent nor more infective than the parent. Furthermore, coagulase did not increase the pathogenicity of clfA-positive streptococci when both clfA and coa genes were simultaneously expressed in an artificial minioperon in streptococci. These results definitively attribute a role for ClfA, but not coagulase, in S. aureus endovascular infections. This gain-of-function strategy might help solve the role of individual factors in the complex the S. aureus-host relationship.