Les amyloses, un modèle de maladie du repliement des protéines

Longtemps considérée comme une maladie unique, l'amylose est aujourd'hui reconnue comme la marque histologique d'un ensemble de maladies, les amyloses. L'amylose est la voie finale commune, chez l'homme et dans de nombreuses espèces animales, de l'agrégation pathologique de plus de vingt protéines appartenant à des familles dénuées de relation fonctionnelle ou structurale. Les mécanismes de formation de ces agrégats commencent à être mieux connus. L'étape centrale, que l'on peut artificiellement reproduire in vitro, est un changement de conformation d'une protéine native en une protéine apte à l'auto-agrégation, sous une forme essentiellement formée de feuillets β. Le traitement actuel des amyloses, qui consiste à réduire la disponibilité en protéine amyloïde, n'est pas pleinement satisfaisant. La reconnaissance progressive des différentes étapes de ce phénomène pathologique a conduit à la conception de cibles thérapeutiques nouvelles : stabilisation de la protéine native, désagrégation des structures déjà β-plissées ou, encore, inhibition des liaisons avec certains composants du tissu conjonctif. Différentes approches, pharmacologiques et immunologiques, sont à l'étude sur des systèmes cellulaires et des modèles animaux, et certaines molécules sont parvenues au stade de l'essai clinique chez l'homme.Amyloidosis bears many characteristics of orphan diseases. Its diagnosis is difficult and often delayed. The main reasons thereof are its quite various clinical presentation: amyloidosis behaves as a new great masquerader, and the need to get a tissue sample to submit to specific dyes. Although we have been able for a long time to recognize amyloid, its intimate nature has remained quite completely enigmatic until recently. In fact, major advances in this way have appeared only in the last decade and it is now possible to consider the mechanisms of amyloidosis as a multistep phenomenon. Amyloidosis is no more thought only as a « storage disease » of the extracellular space. This archaic viewpoint has shifted to the emerging paradigm of misfolded protein disorders. Amyloid proteins thus appear as a subgroup of misfolded proteins, where misfolding leads to subsequent aggregation. This aggregation may be a generic property of polypeptide chains possibly linked to their common peptide backbone that does not depend on specific amino acid sequences. And, in fact, many proteins can in vitro form amyloid-like aggregates, while in vivo, only 20 amyloid proteins have been so far identified. Although misfolding and aggregation are quite well studied in vitro, the last step of amyloid deposition, i.e. anchorage to the extracellular matrix, can not be so easily approached. Proteoglycans and serum amyloid P component have nevertheless been identified as key elements involved in extracellular deposition of amyloid proteins. These advances have opened new avenues in the therapeutic of amyloid disorders. Current treatment consists of support or replacement of impaired organ function and measures to reduce the production of amyloidogenic precursor proteins. Potential novel therapeutic strategies include stabilisation of the native fold of precursor proteins with targeted small molecules, reversion of misfolded proteins to their native state with « beta-sheet breakers », inhibition of amyloid fibril propagation and enhancement of amyloid clearance either through immunotherapy or by reducing the stability of deposits through depletion of serum amyloid P component, and breaking the anchorage to the extracellular matrix with glycosaminoglycan analogs

Résidence, tenure foncière, alliance dans une société bilinéaire (Sérèr du Sine et du Baol, Sénégal)

M. Dupire, A. Lericollais, B. Delpech et J.-M. Gastellu — Residence, Land Tenure and Marriage in a Double-Descent Society: The Serer from the Sine and Baol Regions of Senegal. This society is characterized by virilocal residence, double-descent, and matrilineal inheritance of non-consumable goods. Residential compounds are inherited in both the agnatic and the uterine lines, the relative proportion of each type of succession varying in the four villages under study. A compound may be divided into 'wards', 'kitchens', and, further down, 'uterine huts', each of these units corresponding to a specifie economic function. Starting from K. Gough's five types of residential categories, we define seven different patterns, the form most frequently found being the patrilocal extended family, the elementary family and a composite type of avuncular family, in that order. There is a significant correlation between residence patterns and inheritance of traditional offices. 'Kitchens' differ from compounds insofar as they can be matrilocal and chiefly consist of elementary families. While married sons often live in the same 'kitchen' with their fathers, nephews seldom cohabit with their MB. The 'uterine hut' is the primary unit of economic accumulation. The bilineal pattern of inheritance is also found in the four-level System of land-rights, with a correlation between land-rights and residence. Residential patterns and pre-ferential marriages tend to counterbalance the dispersal of a matrilineage's women resulting from virilocality.Dupire Marguerite, Lericollais André, Delpech Bernard, Gastellu Jean-Marc. Résidence, tenure foncière, alliance dans une société bilinéaire (Serer du Sine et du Baol, Sénégal).. In: Cahiers d'études africaines, vol. 14, n°55, 1974. pp. 417-452

Early calcium increase triggers the formation of olfactory long-term memory in honeybees

<p>Abstract</p> <p>Background</p> <p>Synaptic plasticity associated with an important wave of gene transcription and protein synthesis underlies long-term memory processes. Calcium (Ca²⁺) plays an important role in a variety of neuronal functions and indirect evidence suggests that it may be involved in synaptic plasticity and in the regulation of gene expression correlated to long-term memory formation. The aim of this study was to determine whether Ca²⁺is necessary and sufficient for inducing long-term memory formation. A suitable model to address this question is the Pavlovian appetitive conditioning of the proboscis extension reflex in the honeybee <it>Apis mellifera, </it>in which animals learn to associate an odor with a sucrose reward.</p> <p>Results</p> <p>By modulating the intracellular Ca²⁺concentration ([Ca²⁺]i) in the brain, we show that: (i) blocking [Ca²⁺]i increase during multiple-trial conditioning selectively impairs long-term memory performance; (ii) conversely, increasing [Ca²⁺]i during single-trial conditioning triggers long-term memory formation; and finally, (iii) as was the case for long-term memory produced by multiple-trial conditioning, enhancement of long-term memory performance induced by a [Ca²⁺]i increase depends on <it>de novo </it>protein synthesis.</p> <p>Conclusion</p> <p>Altogether our data suggest that during olfactory conditioning Ca²⁺is both a necessary and a sufficient signal for the formation of protein-dependent long-term memory. Ca²⁺therefore appears to act as a switch between short- and long-term storage of learned information.</p

Kallmann Syndrome: Mutations in the Genes Encoding Prokineticin-2 and Prokineticin Receptor-2

Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome

E4F1-mediated control of pyruvate dehydrogenase activity is essential for skin homeostasis.

The multifunctional protein E4 transcription factor 1 (E4F1) is an essential regulator of epidermal stem cell (ESC) maintenance. Here, we found that E4F1 transcriptionally regulates a metabolic program involved in pyruvate metabolism that is required to maintain skin homeostasis. E4F1 deficiency in basal keratinocytes resulted in deregulated expression of dihydrolipoamide acetyltransferase (Dlat), a gene encoding the E2 subunit of the mitochondrial pyruvate dehydrogenase (PDH) complex. Accordingly, E4f1 knock-out (KO) keratinocytes exhibited impaired PDH activity and a redirection of the glycolytic flux toward lactate production. The metabolic reprogramming of E4f1 KO keratinocytes associated with remodeling of their microenvironment and alterations of the basement membrane, led to ESC mislocalization and exhaustion of the ESC pool. ShRNA-mediated depletion of Dlat in primary keratinocytes recapitulated defects observed upon E4f1 inactivation, including increased lactate secretion, enhanced activity of extracellular matrix remodeling enzymes, and impaired clonogenic potential. Altogether, our data reveal a central role for Dlat in the metabolic program regulated by E4F1 in basal keratinocytes and illustrate the importance of PDH activity in skin homeostasis

Injecting drug use predicts active tuberculosis in a national cohort of people living with HIV

OBJECTIVES: Tuberculosis (TB) is common in people living with HIV, leading to worse clinical outcomes including increased mortality. We investigated risk factors for developing TB following HIV diagnosis. DESIGN: Adults aged at least 15 years first presenting to health services for HIV care in England, Wales or Northern Ireland from 2000 to 2014 were identified from national HIV surveillance data and linked to TB surveillance data. METHODS: We calculated incidence rates for TB occurring more than 91 days after HIV diagnosis and investigated risk factors using multivariable Poisson regression. RESULTS: A total of 95 003 adults diagnosed with HIV were followed for 635 591 person-years; overall incidence of TB was 344 per 100 000 person-years (95% confidence interval 330-359). TB incidence was high for people who acquired HIV through injecting drugs [PWID; men 876 (696-1104), women 605 (365-945)] and black Africans born in high TB incidence countries [644 (612-677)]. The adjusted incidence rate ratio for TB amongst PWID was 4.79 (3.35-6.85) for men and 6.18 (3.49-10.93) for women, compared with MSM. The adjusted incidence rate ratio for TB in black Africans from high-TB countries was 4.27 (3.42-5.33), compared with white UK-born individuals. Lower time-updated CD4 cell count was associated with increased rates of TB. CONCLUSION: PWID had the greatest risk of TB; incidence rates were comparable with those in black Africans from high TB incidence countries. Most TB cases in PWID were UK-born, and likely acquired TB through transmission within the United Kingdom. Earlier HIV diagnosis and quicker initiation of antiretroviral therapy should reduce TB incidence in these populations