The discovery of “molecular chaperones” has dramatically changed our concept of cellular protein folding. Rather than folding spontaneously, most newly synthesized polypeptide chains seem to acquire their native conformation in a reaction mediated by these versatile helper proteins. Understanding the structure and function of molecular chaperones is likely to yield useful applications for medicine and biotechnology in the future.

Self‐renewal and differentiation of stem cells are tightly regulated processes subject to intrinsic and extrinsic signals. Molecular chaperones and co‐chaperones, especially heat shock proteins (Hsp), are ubiquitous molecules involved in the modulation of protein conformational and complexation states. The function of Hsp, which are typically associated with stress response and tolerance, is well characterized in differentiated cells, while their role in stem cells remains unclear. It appears that embryonic stem cells exhibit increased stress tolerance and concomitant high (...) levels of chaperone expression. This review critically evaluates stem cell research from a molecular chaperone perspective. Furthermore, we propose a model of chaperone‐modulated self‐renewal in mouse embryonic stem cells. (shrink)

Molecular chaperones assist de novo protein folding and facilitate the refolding of stress‐denatured proteins. The molecular chaperone concept was coined nearly 35 years ago, and since then, tremendous strides have been made in understanding how these factors support protein folding. Here, we focus on how various chaperone proteins were first identified to play roles in protein folding. Examples are used to illustrate traditional routes of chaperone discovery and point out their advantages and limitations. Recent advances, including the (...) development of folding biosensors and promising methods for the stabilization of proteins in vivo, provide new routes for chaperone discovery. (shrink)

In this paper I use a case study—the discovery of the chaperon function exerted by proteins in the various steps of the hereditary process—to re-discuss the question whether the nucleic acids are the sole repositories of relevant information as assumed in the information theory of heredity. The evidence I here present of a crucial role for molecular chaperones in the folding of nascent proteins, as well as in DNA duplication, RNA folding and gene control, suggests that the family (...) of proteins acting as molecular chaperones provides information that is complementary to that stored in the nucleic acids, and equally important. A re-evaluation of the role of proteins in the hereditary process is in order away from the gene-centric approach of the information theory of heredity, to which neo-Darwinian evolutionists adhere. (shrink)

Yvonne Knibiehler continue son histoire des mères commencée il y a quelques années et arrêtée au seuil des ses propres enfantements, comme elle le rappelle dans l'introduction. L'entreprise n'est pourtant pas aisée. Non pas que le sujet déborderait trop sur l'intime de la chercheuse. L'égo-histoire, qui ne rime décidément pas avec l'histoire tout court, ne dépasse pas les premières pages de l'ouvrage. Mais le sujet est miné, piégé de l'intérieur par une charge idéologique hors du commu..

Yvonne Knibiehler continue son histoire des mères commencée il y a quelques années et arrêtée au seuil des ses propres enfantements, comme elle le rappelle dans l'introduction. L'entreprise n'est pourtant pas aisée. Non pas que le sujet déborderait trop sur l'intime de la chercheuse. L'égo-histoire, qui ne rime décidément pas avec l'histoire tout court, ne dépasse pas les premières pages de l'ouvrage. Mais le sujet est miné, piégé de l'intérieur par une charge idéologique hors du commu...

Dès que Le Deuxième sexe de Simone de Beauvoir paraît en France en 1949, il est pris dans la division intellectuelle de la guerre froide. Mais est-ce le cas dans le reste de l’Europe à mesure que les traductions du livre paraissent? Une comparaison des réceptions et traductions du livre au cours de la guerre froide manque. Elle est pourtant rendue possible grâce à trois récents tournants historiographiques : la guerre froide au prisme du genre, l’étude des circulations transnationales du (...) Deuxième sexe et la traductologie féministe. (shrink)

L'histoire des femmes depuis la Seconde Guerre mondiale est bien plus développée en Italie qu'en France. Le dernier ouvrage d'Anna Rossi-Doria nous en fournit une preuve supplémentaire. S'appuyant sur ses recherches personnelles, mais aussi sur une solide bibliographie, l'auteure s'interroge sur les multiples facettes du droit de vote féminin. Le décret qui institue le droit de vote féminin présente bien des similarités avec l'ordonnance française. Comme en France, celui-ci ne résulte..

L'histoire des femmes depuis la Seconde Guerre mondiale est bien plus développée en Italie qu'en France. Le dernier ouvrage d'Anna Rossi-Doria nous en fournit une preuve supplémentaire. S'appuyant sur ses recherches personnelles, mais aussi sur une solide bibliographie, l'auteure s'interroge sur les multiples facettes du droit de vote féminin. Le décret qui institue le droit de vote féminin présente bien des similarités avec l'ordonnance française. Comme en France, celui-ci ne résulte...

Depuis les années 1980, l’histoire de la médecine a connu un très fort renouvellement de ses approches, de ses objets et de sa mise en récit. L’histoire des femmes, du genre et des sexualités, en plein essor depuis ces mêmes années, a contribué de manière non négligeable à ce renouvellement en s’emparant de sources médicales délaissées par l’histoire de la médecine traditionnelle. En effet, durablement imprégnées par l’héritage positiviste du xixe siècle, l’histoire de la médecine et plus lar...

Ce gros livre est le fruit d’un travail collectif, réalisé à l’initiative de l’Agence nationale de recherche sur le sida et les hépatites virales (ANRS), par un collectif de treize chercheur-e-s (sociologues, démographes, épidémiologistes, psycho-sociologues, économistes). Un long questionnaire a été élaboré et soumis par téléphone par soixante et un enquêteurs de l’Institut de sondage Ipsos à plus de 12 000 personnes âgées de 18 à 69 ans entre septembre 2005 et mars 2006. Cette enquête dite...

Durant les années 1950 et plus encore la décennie suivante, les ouvrages sur les questions féminines se multiplient. Cet article s’interroge sur les auteures de ces essais. Se dessine ainsi une génération d’expertes en études sur les femmes. Nées au début du siècle, profondément marquées par l’expérience de la deuxième guerre, ces nouvelles spécialistes sont diplômées des universités. Elles bénéficient de l’essor des médias mais ne parviennent pas toujours à avoir une situation professionnelle stable. Ensemble et s’appuyant sur les réflexions (...) beauvoiriennes, elles construisent un nouveau champ d’études, dont nous sommes les héritières. (shrink)

Pour celles et ceux qui ne connaîtraient pas ou peu, ou mal Marie-France Brive, ce livre offre l'occasion de multiples rencontres émouvantes avec l'une des figures majeures de l'histoire des femmes en France. Car, comme son titre ne l'indique pas, cet ouvrage collectif est un hommage posthume. Ironie de l'histoire, le nom de celle qui affirmait : « il y a une construction de l'oubli des femmes en histoire » (p. 333) se trouve ainsi effacé de la couverture du livre (...) qui lui est consacré.... (shrink)

L'ouvrage de William Guéraiche s'inscrit dans un renouvellement notable de l'historiographie de ces quelques dernières années. L'après-Deuxième Guerre mondiale, les années cinquante se voient revisitées de multiples façons par les travaux de Noël Burch et Geneviève Sellier, Luc Capdevila, Fabrice Virgili et moi-même. Le découpage chronologique de l'étude ne suit pas les coupures majeures de l'histoire politique française; ni 1958 ni 1968 ne fondent de ruptures, par exemple. La superpos...

Cet ouvrage reprend sous forme remaniée les actes du colloque « Germaine Poinso-Chapuis, témoin de son temps » organisé à Marseille par l'association Les Femmes et la Ville (20-22 novembre 1997). Il répare heureusement l'oubli injuste d'une figure majeure de l'histoire de l'après-guerre. Moins connue que les femmes sous-secrétaires d'État du Front populaire alors qu'elle est la première femme ministre de plein exercice, moins populaire que Simone Veil alors qu'elle a été députée pendan...

Sans prétendre faire œuvre exhaustive ni même définitive, Mariette Sineau et Evelyne Tardy se livrent à un instructif travail comparatif sur le droit des femmes dans les deux territoires francophones. Malgré toutes leurs différences, ceux-ci se montrent suffisamment proches pour soutenir la comparaison. Tous deux adoptent le code civil napoléonien (en 1866 pour le Québec pourtant cerné par la bien plus progressive common law), tous deux sont également à forte dominante catholique. Le m..

Sans prétendre faire œuvre exhaustive ni même définitive, Mariette Sineau et Evelyne Tardy se livrent à un instructif travail comparatif sur le droit des femmes dans les deux territoires francophones. Malgré toutes leurs différences, ceux-ci se montrent suffisamment proches pour soutenir la comparaison. Tous deux adoptent le code civil napoléonien (en 1866 pour le Québec pourtant cerné par la bien plus progressive common law), tous deux sont également à forte dominante catholique. Le m...

Exceptionnel, l'itinéraire politique de Marcelle Devaud, l'est assurément. Sénatrice dès 1946 puis députée (de 1958 à 1962), maire de Colombes (1959-1965), membre de Conseil Economique et Social (1962-1979), représentante de la France à la commission de la femme aux Nations-Unies (1975-1983), elle cumule tous ces mandats avec de nombreuses responsabilités dans les associations féminines, dont plusieurs fondées par elle-même. Quand on sait qu'elle est par ailleurs mère de 6 enfants, on ..

Exceptionnel, l'itinéraire politique de Marcelle Devaud, l'est assurément. Sénatrice dès 1946 puis députée (de 1958 à 1962), maire de Colombes (1959-1965), membre de Conseil Economique et Social (1962-1979), représentante de la France à la commission de la femme aux Nations-Unies (1975-1983), elle cumule tous ces mandats avec de nombreuses responsabilités dans les associations féminines, dont plusieurs fondées par elle-même. Quand on sait qu'elle est par ailleurs mère de 6 enfants, on...

Molecular chaperones in cells constantly monitor and bind to exposed hydrophobicity in newly synthesized proteins and assist them in folding or targeting to cellular membranes for insertion. However, proteins can be misfolded or mistargeted, which often causes hydrophobic amino acids to be exposed to the aqueous cytosol. Again, chaperones recognize exposed hydrophobicity in these proteins to prevent nonspecific interactions and aggregation, which are harmful to cells. The chaperone‐bound misfolded proteins are then decorated with ubiquitin chains denoting them (...) for proteasomal degradation. It remains enigmatic how molecular chaperones can mediate both maturation of nascent proteins and ubiquitination of misfolded proteins solely based on their exposed hydrophobic signals. In this review, we propose a dynamic ubiquitination and deubiquitination model in which ubiquitination of newly synthesized proteins serves as a “fix me” signal for either refolding of soluble proteins or retargeting of membrane proteins with the help of chaperones and deubiquitinases. Such a model would provide additional time for aberrant nascent proteins to fold or route for membrane insertion, thus avoiding excessive protein degradation and saving cellular energy spent on protein synthesis. Also see the video abstract here: https://youtu.be/gkElfmqaKG4. (shrink)

The rapidly changing field of genetics affects society through advances in health-care and through implications of genetic research. This study addresses the impacts of new genetic discoveries and technologies on different segments of today's society. The book begins with a chapter on genetic complexity, and subsequent chapters discuss moral and ethical questions arising from today's genetics from the perspectives of health care professionals, the media, the general public, special interest groups and commercial interests.

Molecular chaperones facilitate the correct folding of other proteins under physiological and stress conditions. Recently it has become evident that various co‐chaperone proteins regulate the cellular functions of these chaperones, particularly Hsp70 and Hsp90. Hop is one of the most extensively studied co‐chaperones that is able to directly associate with both Hsp70 and Hsp90. The current dogma proposes that Hop functions primarily as an adaptor that directs Hsp90 to Hsp70‐client protein complexes in the cytoplasm. However, recent (...) evidence suggests that Hop can also modulate the chaperone activities of these Hsps, and that it is not dedicated to Hsp70 and Hsp90. While the co‐chaperone function of Hop within the cytoplasm has been extensively studied, its association with nuclear complexes and prion proteins remains to be elucidated. This article will review the structural features of Hop, and the evidence that its biological function is considerably broader than previously envisaged. BioEssays 26:1058–1068, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Protein disulfide isomerase (PDI) is one of the most abundant and critical protein folding catalysts in the endoplasmic reticulum of eukaryotic cells. PDI consists of four thioredoxin domains and interacts with a wide range of substrate and partner proteins due to its intrinsic conformational flexibility. PDI plays multifunctional roles in a variety of pathophysiological events, both as an oxidoreductase and a molecular chaperone. Recent studies have revealed that the conformation and activity of PDI can be regulated in multiple ways, (...) including posttranslational modification and substrate/ligand binding. Here, we summarize recent advances in understanding the function and regulation of PDI in different pathological and physiological events. We propose that the multifunctional roles of PDI are regulated by multiple mechanisms. Furthermore, we discuss future directions for the study of PDI, emphasizing how different regulatory modes are linked to the conformational changes and biological functions of PDI in the context of diverse pathophysiologies. (shrink)

The environmentally responsive molecular chaperone Hsp90 assists the maturation of many key regulatory proteins. An unexpected consequence of this essential biochemical function is that genetic variation can accumulate in genomes and can remain phenotypically silent until Hsp90 function is challenged. Notably, this variation can be revealed by modest environmental change, establishing an environmentally responsive exposure mechanism. The existence of diverse cryptic polymorphisms with a plausible exposure mechanism in evolutionarily distant lineages has implications for the pace and nature of evolutionary (...) change. Chaperone‐mediated storage and release of genetic variation is undoubtedly rooted in protein‐folding phenomena. As we discuss, proper protein folding crucially affects the trajectory from genotype to phenotype. Indeed, the impact of protein quality‐control mechanisms and other fundamental cellular processes on evolution has heretofore been overlooked. A true understanding of evolutionary processes will require an integration of current evolutionary paradigms with the many new insights accruing in protein science. BioEssays 26:348–362, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The coupling of protein synthesis and folding is a crucial yet poorly understood aspect of cellular protein folding. Over the past few years, it has become possible to experimentally follow and define protein folding on the ribosome, revealing principles that shape co‐translational folding and distinguish it from refolding in solution. Here, we highlight some of these recent findings from biochemical and biophysical studies and their potential significance for cellular protein biogenesis. In particular, we focus on nascent chain interactions with the (...) ribosome, interactions within the nascent protein, modulation of translation elongation rates, and the role of mechanical force that accompanies nascent protein folding. The ability to obtain mechanistic insight in molecular detail has set the stage for exploring the intricate process of nascent protein folding. We believe that the aspects discussed here will be generally important for understanding how protein synthesis and folding are coupled and regulated. (shrink)

The process of protein folding in the cell is now known to depend on the action of other proteins. These proteins include molecular chaperones, Which interact non‐covalently with proteins as they fold and improve the final yields of active protein in the cell. The precise mechanism by which molecular chaperones act is obscure. Experiments reported recently(1) show that for one molecular chaperone (Cpn60, typified by the E. coli protein GroEL), the folding reaction is driven by (...) cycles of binding and release of the co‐chaperone Cpn10 (known as GroES in E. coli). These alternate with binding and release of the unfolded protein substrate. These cycles come about because of the opposite effects of Cpn10 and unfolded protein on the Cpn60 complex: the former stabilises the ADP‐bound state of Cpn60, whereas the latter stimulates ADP‐ATP exchange. This model proposes that the substrate protein goes through multiple cycles of binding and release, and is released into the cavity of the Cpn60 complex where it can undergo folding without interacting with other nearby folding intermediates. This is consistent with the ability of Cpn60 proteins to enhance folding by blocking pathways to aggregation. (shrink)

In addition to their function in transport of water, ions, small metabolites, and growth factors in normal plant tissue, the plasmodesmata presumably serve as routes for cell‐to‐cell movement of plant viruses in infected tissue. Virus cell‐to‐cell spread through plasmodesmata is an active process mediated by specialized virus encoded movement proteins; however, the mechanism by which these proteins operate is not clear. We incorporate recent information on the biochemical properties of plant virus movement proteins and their interaction with plasmodesmata in a (...) model for transport of nucleic acids through plasmodesmatal channels. We propose that only single stranded (ss) nucleic acids can be transported efficiently through plasmodesmata, and that movement proteins function as molecular chaperones for ss nucleic acids to form unfolded movement protein‐ss nucleic acid complexes. These complexes are targeted to plasmodesmata. Plasmodesmatal permeability is then increased following interaction with movement protein and the entire movement complex or its nucleic acid component is translocated across the plasmodesmatal channel. (shrink)

Regulation of microtubule (MT) dynamics is essential for many cellular processes, but the machinery that controls MT dynamics remains poorly understood. MT plus‐end tracking proteins (+TIPs) are a set of MT‐associated proteins that dynamically track growing MT ends and are uniquely positioned to govern MT dynamics. +TIPs associate with each other in a complex array of inter‐ and intra‐molecular interactions known as the “+TIP network.” Why do so many +TIPs bind to other +TIPs? Typical answers include the ideas that (...) these interactions localize proteins where they are needed, deliver proteins to the cortex, and/or create regulatory pathways. We propose an additional and more mechanistic hypothesis: that +TIPs bind each other to create a superstructure that promotes MT assembly by constraining the structural fluctuations of the MT tip, thus acting as a polymerization chaperone. (shrink)

This review portraits FK506 binding protein (FKBP) 51 as “reactivity protein” and collates recent publications to develop the concept of FKBP51 as contributor to different levels of adaptation. Adaptation is a fundamental process that enables unicellular and multicellular organisms to adjust their molecular circuits and structural conditions in reaction to environmental changes threatening their homeostasis. FKBP51 is known as chaperone and co‐chaperone of heat shock protein (HSP) 90, thus involved in processes ensuring correct protein folding in response to proteotoxic (...) stress. In mammals, FKBP51 both shapes the stress response and is calibrated by the stress levels through an ultrashort molecular feedback loop. More recently, it has been linked to several intracellular pathways related to the reactivity to drug exposure and stress. Through its role in autophagy and DNA methylation in particular it influences adaptive pathways, possibly also in a transgenerational fashion.Also see the video abstract here. (shrink)

There are two facets to the central dogma proposed by Francis Crick in 1957. One concerns the relation between the sequence of nucleotides and the sequence of amino acids, the second is devoted to the relation between the sequence of amino acids and the native three-dimensional structure of proteins. 'Folding is simply a function of the order of the amino acids,' i.e. no information is required for the proper folding of a protein other than the information contained in its sequence. (...) This protein side of the central dogma was elaborated in a scientific context in which the characteristics and functions of proteins, and the mechanisms of protein folding, were seen very differently. This context, which made the folding problem a simple one, supported the bold proposition of Francis Crick. The protein side of the central dogma was not challenged by the discovery of prions if one adopts the definition of information given by Francis Crick. It might have been challenged by the discovery that regulatory enzymes exist in different conformations, and the evidence for the existence of chaperones assisting protein folding. But it was not, and folding remains what it was for Francis Crick, 'simply a function of the order of amino acids'. But the meaning of 'function' has dramatically changed. It is no longer the result of simple physicochemical laws, but that of a long evolutionary process which has optimized protein folding. Molecular mechanistic explanations have to be allied with evolutionary explanations, in a way characteristic of present biology. (shrink)

Mitochondrial function is key for maintaining cellular health, while mitochondrial failure is associated with various pathologies, including inherited metabolic disorders and age‐related diseases. In order to maintain mitochondrial quality, several pathways of mitochondrial quality control have evolved. These systems monitor mitochondrial integrity through antioxidants, DNA repair systems, and chaperones and proteases involved in the mitochondrial unfolded protein response. Additional regulation of mitochondrial function involves dynamic exchange of components through mitochondrial fusion and fission. Sustained stress induces a selective autophagy – (...) termed mitophagy – and ultimately leads to apoptosis. Together, these systems form a network that acts on the molecular, organellar, and cellular level. In this review, we highlight how these systems are regulated in an integrated context‐ and time‐dependent network of mitochondrial quality control that is implicated in healthy aging. (shrink)

Vacuolar ATPases (V‐ATPases, V1Vo‐ATPases) are rotary motor proton pumps that acidify intracellular compartments, and, when localized to the plasma membrane, the extracellular space. V‐ATPase is regulated by a unique process referred to as reversible disassembly, wherein V1‐ATPase disengages from Vo proton channel in response to diverse environmental signals. Whereas the disassembly step of this process is ATP dependent, the (re)assembly step is not, but requires the action of a heterotrimeric chaperone referred to as the RAVE complex. Recently, an alternative pathway (...) of holoenzyme disassembly was discovered that involves binding of Oxidation Resistance 1 (Oxr1p), a poorly characterized protein implicated in oxidative stress response. Unlike conventional reversible disassembly, which depends on enzyme activity, Oxr1p induced dissociation can occur in absence of ATP. Yeast Oxr1p belongs to the family of TLDc domain containing proteins that are conserved from yeast to mammals, and have been implicated in V‐ATPase function in a variety of tissues. This brief perspective summarizes what we know about the molecular mechanisms governing both reversible (ATP dependent) and Oxr1p driven (ATP independent) V‐ATPase dissociation into autoinhibited V1 and Vo subcomplexes. (shrink)

Proteinaceous stalks produced by Gram‐negative bacteria are often used to adhere to environmental surfaces. Among them, chaperone‐usher (CU) fimbriae adhesins, related to prototypical type 1 fimbriae, interact in highly specific ways with different ligands at different stages of bacterial infection or surface colonisation. Recent analyses revealed a large number of potential and often “cryptic” CU fimbriae homologues in the genome of commensal and pathogenic Escherichia coli and closely related bacteria. We propose that CU fimbriae form a yet unexplored arsenal of (...) lectins, carbohydrate‐binding proteins involved in various aspects of bacterial surface adhesion and tissue tropism. Combined efforts of molecular and structural biologists will be required to unravel the biological contribution of the bacterial lectome, however, current progress has already opened up new perspectives in the design of novel anti‐infective strategies. (shrink)

Intermediate filaments, which form the structural framework of both the cytoskeleton and the nuclear lamina in most eukaryotic cells, have been found to be highly dynamic structures. A continuous exchange of subunit proteins at the filament surface and a stabilisation of soluble subunits by chaperone‐type proteins may modulate filament structure and plasticity. Recent studies on the cell cycle‐dependent interaction of intermediate filaments with associated proteins, and a detailed analysis of intermediate filament phosphorylation in defined subcellular locations at various stages of (...) mitosis, have brought new insights into the molecular mechanisms involved in the mitotic reorganisation of intermediate filaments. Some of these studies have allowed new speculations about the possible cellular functions of cytoplasmic intermediate filaments, and increased our understanding of the specific functions of the lamins and the lamina‐associated membrane proteins in the post‐mitotic reassembly of the nucleus. (shrink)

Outer membrane proteins (OMPs) maintain the viability of Gram‐negative bacteria by functioning as receptors, transporters, ion channels, lipases, and porins. Folding and assembly of OMPs involves synchronized action of chaperones and multi‐protein machineries which escort the highly hydrophobic polypeptides to their target outer membrane in a folding competent state. Previous studies have identified proteins and their involvement along the OMP biogenesis pathway. Yet, the mechanisms of action and the intriguing ability of all these molecular machines to work without (...) the typical cellular energy source of ATP, but solely based on thermodynamic principles, are still not well understood. Here, we highlight how different single‐molecule studies can shed additional light on the mechanisms and kinetics of OMP biogenesis. (shrink)

We highlight a recent study exploring the hand‐off of UV damage to several key nucleotide excision repair (NER) proteins in the cascade: UV‐DDB, XPC and TFIIH. The delicate dance of DNA repair proteins is choreographed by the dynamic hand‐off of DNA damage from one recognition complex to another damage verification protein or set of proteins. These DNA transactions on chromatin are strictly chaperoned by post‐translational modifications (PTM). This new study examines the role that ubiquitylation and subsequent DDB2 degradation has during (...) this process. In total, this study suggests an intricate cellular timer mechanism that under normal conditions DDB2 helps recruit and ubiquitylate XPC, stabilizing XPC at damaged sites. If DDB2 persists at damaged sites too long, it is turned over by auto‐ubiquitylation and removed from DNA by the action of VCP/p97 for degradation in the 26S proteosome. (shrink)

Fibrillar protein aggregates are the pathological hallmark of a group of age‐dependent neurodegenerative conditions, including Alzheimer's and Parkinson's disease. Aggregates of the microtubule‐associated protein Tau are observed in Alzheimer's disease and primary tauopathies. Tau pathology propagates from cell to cell in a prion‐like process that is likely subject to modulation by extracellular chaperones such as Clusterin. We recently reported that Clusterin delayed Tau fibril formation but enhanced the activity of Tau oligomers to seed aggregation of endogenous Tau in a (...) cellular model. In contrast, Clusterin inhibited the propagation of α‐Synuclein aggregates associated with Parkinson's disease. These findings raise the possibility of a mechanistic link between Clusterin upregulation observed in Alzheimer's disease and the progression of Tau pathology. Here we review the diverse functions of Clusterin in the pathogenesis of neurodegenerative diseases, focusing on evidence that Clusterin may act either as a suppressor or enhancer of pathology. (shrink)

Histone variants are specialized histones which replace their canonical counterparts in specific nucleosomes. Together with histone post‐translational modifications and DNA methylation, they contribute to the epigenome. Histone variants are incorporated at specific locations by the concerted action of histone chaperones and ATP‐dependent chromatin remodelers. Recent studies have shown that the histone chaperone FACT plays key roles in preventing pervasive incorporation of two histone variants: H2A.Z and CenH3/CENP‐A. In addition, Spt6, another histone chaperone, was also shown to be important for (...) appropriate H2A.Z localization. FACT and Spt6 are both associated with elongating RNA polymerase II. Based on these two examples, we propose that the establishment and maintenance of histone variant genomic distributions depend on a transcription‐coupled epigenome editing (or surveillance) function of histone chaperones. (shrink)

Background: Medical chaperones (MC) are underutilised. The influence of Islamic culture on the use of MC is not known. Aim: To examine physicians’ use and perception of MC in Islamic culture. Setting: A major tertiary care hospital in Saudi Arabia. Methods: 315 self-administered questionnaires were distributed to attendees of grand rounds of 13 departments. Results: 186 (59%) questionnaires were completed. 64.5% of the respondents were 30–49 years old, 75.8% were men and 31.2% were in training; 79% had a clinic (...) load of under 50 patients per week and 47.8% had postgraduate training (PGT) in an Islamic country. MC were reported to be infrequently (⩽25% of the time) used by 44.1% (69.2% female vs 39% male physicians, p = 0.001; 58.6% in training vs 36.8% attending, p = 0.007; 52.1% PGT in Islamic vs 35.6% in western countries, p = 0.027), offered by 52.7% (78.9% female vs 46.8% male physicians, p<0.001) and requested by 79% of patients. MC were reported to be commonly (>75% of the time) used, offered by physicians and requested by patients by 38.2%, 29% and 7.5% of respondents, respectively. The most frequently cited reasons for not using MC were privacy/confidentiality (36.6%) and understaffing (30.5%). Equal numbers of respondents perceived MC use as a protection for physicians or patients (67.7% and 65.6%, respectively). Conclusions: MC are underutilised even in Islamic culture, especially among female physicians. Training in western countries is favourably associated with MC use. Underutilisation appears to be related to privacy/confidentiality, understaffing and failure of patients to request a MC. (shrink)

Cet ouvrage comble un vide dans l'histoire des femmes et du féminisme, qui ne s'était guère intéressée jusqu'ici à la période qui va de 1945 à 1970, à l'exception de travaux comme ceux de Dominique Loiseau sur le militantisme des femmes à Nantes ou notre recherche commune ­ Michelle Zancarini-Fournel et moi-même ­ sur des parcours de femmes à Saint-Étienne, incluant les années 1950. Grâce à ce livre, nous disposons maintenant, d'une bibliographie assez complète sur le féminisme françai...

Le mot sexologie, la science de la sexualité, apparaît en France au début des années 1910. Il marque, de la part de ceux qui en usent, la volonté à la fois de lutter pour l’égalité des droits en matière de pratiques sexuelles et de rompre avec le savoir médical sur la sexualité. Dans son livre Les origines de la sexologie, 1850-1900, Sylvie Chaperon explore ce champ nouveau de l’histoire et se propose de démêler les fils qui, en ce domaine, enchevêtrent (...) si fortement savoir, pouvoir et représe... (shrink)

Despite the transformation in biological practice and theory brought about by discoveries in molecular biology, until recently philosophy of biology continued to focus on evolutionary biology. When the Human Genome Project got underway in the late 1980s and early 1990s, philosophers of biology -- unlike historians and social scientists -- had little to add to the debate. In this landmark collection of essays, Sahotra Sarkar broadens the scope of current discussions of the philosophy of biology, viewing molecular biology (...) as a unifying perspective on life that complements that of evolutionary biology. His focus is on molecular biology, but the overriding question behind these papers is what molecular biology contributes to all traditional areas of biological research.Molecular biology -- described with some foresight in a 1938 Rockefeller Foundation report as a branch of science in which "delicate modern techniques are being used to investigate ever more minute details" -- and its modeling strategies apparently argue in favor of physical reductionism. Sarkar's first three chapters explore reductionism -- defending it, but cautioning that reduction to molecular interactions is not necessarily a reduction to genetics. The next sections of the book discuss function, exploring how functional explanations pose a problem for reductionism; the informational interpretation of biology and how it interacts with reductionism; and the tension between the unifying framework of molecular biology and the received framework of evolutionary theory. The concluding chapter is an essay in the emerging field of developmental evolution, exploring what molecular biology may contribute to the transformation of evolutionary theory as evolutionary theory takes into account morphogenetic development. (shrink)

There is consensus within the chemosciences that olfactory perception is of the molecular structure of chemical compounds, yet within philosophical theories of smell there is little agreement about the nature of smell. The paper critically assesses the current state of debate regarding smells within philosophy in the hopes of setting it upon firm scientific footing. The theories to be covered are: Naïve Realism, Hedonic Theories, Process Theory, Odor Theories, and non-Objectivist Theories. The aforementioned theories will be evaluated based on (...) their explanations of the (a) the olfactory quality of a smell, (b) smells as distal entities, and (c) our experience of smells as intentional objects. The paper concludes with a defense of Molecular Structure Theory that demonstrating its superiority in accounting for each of these three aspects of smell. (shrink)