Spontaneous aggregation and global polar ordering in squirmer suspensions

We have developed numerical simulations of three dimensional suspensions of active particles to characterize the capabilities of the hydrodynamic stresses induced by active swimmers to promote global order and emergent structures in active suspensions. We have considered squirmer suspensions embedded in a fluid modeled under a Lattice Boltzmann scheme. We have found that active stresses play a central role to decorrelate the collective motion of squirmers and that contractile squirmers develop significant aggregates.

Reference values and factors associated with renal resistive index in a family-based population study.

Increased renal resistive index (RRI) has been recently associated with target organ damage and cardiovascular or renal outcomes in patients with hypertension and diabetes mellitus. However, reference values in the general population and information on familial aggregation are largely lacking. We determined the distribution of RRI, associated factors, and heritability in a population-based study. Families of European ancestry were randomly selected in 3 Swiss cities. Anthropometric parameters and cardiovascular risk factors were assessed. A renal Doppler ultrasound was performed, and RRI was measured in 3 segmental arteries of both kidneys. We used multilevel linear regression analysis to explore the factors associated with RRI, adjusting for center and family relationships. Sex-specific reference values for RRI were generated according to age. Heritability was estimated by variance components using the ASSOC program (SAGE software). Four hundred women (mean age±SD, 44.9±16.7 years) and 326 men (42.1±16.8 years) with normal renal ultrasound had mean RRI of 0.64±0.05 and 0.62±0.05, respectively (P<0.001). In multivariable analyses, RRI was positively associated with female sex, age, systolic blood pressure, and body mass index. We observed an inverse correlation with diastolic blood pressure and heart rate. Age had a nonlinear association with RRI. We found no independent association of RRI with diabetes mellitus, hypertension treatment, smoking, cholesterol levels, or estimated glomerular filtration rate. The adjusted heritability estimate was 42±8% (P<0.001). In a population-based sample with normal renal ultrasound, RRI normal values depend on sex, age, blood pressure, heart rate, and body mass index. The significant heritability of RRI suggests that genes influence this phenotype.

L'agrégation toxique des protéines: une forme de "delinquance moléculaire" activement combattue dans la cellule par les chaperones moléculaires et les protéases [The toxic aggregation of proteins: a kind of "molecular delinquency" actively fought in the cell by molecular chaperones and proteases]

Under various stresses, mutation-sensitised proteins may spontaneously convert into inactive, aggregation-prone structures, which may be cytotoxic and infectious. In the cell, this new kind of "molecular criminality" is actively fought against by a network of molecular chaperones that can specifically identify, isolate and unfold damaged (delinquent) proteins and favour their subsequent native refolding. Irreversibly damaged molecules unable to natively refold are preferentially "executed" and recycled by proteases. Failing that, they are "imprisoned" within compact amyloids, or "evicted" from the cell. Thus, striking parallels, although of questionable ethical value, exist between protein and human criminality, and between the cellular and social responses to these different types of criminality. Fundamental differences also exist. Whereas programmed death (apoptosis) is the preferred solution chosen by aged and aggregation-stressed cells, collective suicide is seldom an option chosen by lawless human societies. More significantly, there is no clear cellular equivalent for the role of the family and the education system, which are so essential to the proper shaping of functional individuals in the society, and give rise to humanism, that favours crime prevention, reeducation and reinsertion programs over capital punishment. To the cardiologist and transplantation surgeon, the interest of molecular chaperones, in particular of Hsp70, Hsp90 and Hsp27, lays in their ability to inhibit the signalling pathway of programmed cell death. Their induction before and during ischemia, by various treatments and drugs could significantly reduce damages from the post ischemic reperfusion of organs.

Peroxisome proliferator-activated receptors: three isotypes for a multitude of functions.

The peroxisome proliferator-activated receptors (PPARs) are fatty acid and eicosanoid inducible nuclear receptors, which occur in three different isotypes. Upon activator binding, they modulate the expression of various target genes implicated in several important physiological pathways. During the past few years, the identification of both PPAR ligands, natural and synthetic, and PPAR targets and their associated functions has been one of the most important achievements in the field. It underscores the potential therapeutic application of PPAR-specific compounds on the one side, and the crucial biological roles of endogenous PPAR ligands on the other.

Ex vivo characterization of human CD8+ T subsets with distinct replicative history and partial effector functions.

After antigenic challenge, naive T lymphocytes enter a program of proliferation and differentiation during the course of which they acquire effector functions and may ultimately become memory cells. In humans, the pathways of effector and memory T-cell differentiation remain poorly defined. Here we describe the properties of 2 CD8+ T-lymphocyte subsets, RA+CCR7-27+28+ and RA+CCR7-27+28-, in human peripheral blood. These cells display phenotypic and functional features that are intermediate between naive and effector T cells. Like naive T lymphocytes, both subsets show relatively long telomeres. However, unlike the naive population, these T cells exhibit reduced levels of T-cell receptor excision circles (TRECs), indicating they have undergone additional rounds of in vivo cell division. Furthermore, we show that they also share effector-type properties. At equivalent in vivo replicative history, the 2 subsets express high levels of Fas/CD95 and CD11a, as well as increasing levels of effector mediators such as granzyme B, perforin, interferon gamma, and tumor necrosis factor alpha. Both display partial ex vivo cytolytic activity and can be found among cytomegalovirus-specific cytolytic T cells. Taken together, our data point to the presence of T cells with intermediate effector-like functions and suggest that these subsets consist of T lymphocytes that are evolving toward a more differentiated effector or effector-memory stage.

Dual inhibitors of beta-amyloid aggregation and acetylcholinesterase as multi-target anti-Alzheimer drug candidates

Notwithstanding the functional role that the aggregates of some amyloidogenic proteins can play in different organisms, protein aggregation plays a pivotal role in the pathogenesis of a large number of human diseases. One of such diseases is Alzheimer"s disease (AD), where the overproduction and aggregation of the β-amyloid peptide (Aβ) are regarded as early critical factors. Another protein that seems to occupy a prominent position within the complex pathological network of AD is the enzyme acetylcholinesterase (AChE), with classical and non-classical activities involved at the late (cholinergic deficit) and early (Aβ aggregation) phases of the disease. Dual inhibitors of Aβ aggregation and AChE are thus emerging as promising multi-target agents with potential to efficiently modify the natural course of AD. In the initial phases of the drug discovery process of such compounds, in vitro evaluation of the inhibition of Aβ aggregation is rather troublesome, as it is very sensitive to experimental assay conditions, and requires expensive synthetic Aβ peptides, which makes cost-prohibitive the screening of large compound libraries. Herein, we review recently developed multi-target anti-Alzheimer compounds that exhibit both Aβ aggregation and AChE inhibitory activities, and, in some cases also additional valuable activities such as BACE-1 inhibition or antioxidant properties. We also discuss the development of simplified in vivo methods for the rapid, simple, reliable, unexpensive, and high-throughput amenable screening of Aβ aggregation inhibitors that rely on the overexpression of Aβ42 alone or fused with reporter proteins in Escherichia coli.

Gender and socioeconomic disparities in BMI trajectories in the Seychelles using birth cohorts generated from serial population-based surveys.

ABSTRACT: BACKGROUND: The relationship between body mass index (BMI) and socioeconomic status (SES) tends to change over time and across populations. In this study, we examined, separately in men and women, whether the association between BMI and SES changed over successive birth cohorts in the Seychelles (Indian Ocean, African region). METHODS: We used data from all participants in three surveys conducted in 1989, 1994 and 2004 in independent random samples of the population aged 25-64 years in the Seychelles (N= 3'403). We used linear regression to model mean BMI according to age, cohort, SES and smoking status, allowing for a quadratic term for age to account for a curvilinear relation between BMI and age and interactions between SES and age and between SES and cohorts to test whether the relation between SES and BMI changed across subsequent cohorts. All analyses were performed separately in men and women. RESULTS: BMI increased with age in all birth cohorts. BMI was lower in men of low SES than high SES but was higher in women of low SES than high SES. In all SES categories, BMI increased over successive cohorts (1.24 kg/m2 in men and 1.51 kg/m2 for a 10-year increase in birth cohorts, p <0.001). The difference in BMI between men or women of high vs. low SES did not change significantly across successive cohorts (the interaction between SES and year of birth of cohort was statistically not significant). Smoking was associated with lower BMI in men and women (respectively -1.55 kg/m2 and 2.46 kg/m2, p <0.001). CONCLUSIONS: Although large differences exist between men and women, social patterning of BMI did not change significantly over successive cohorts in this population of a middle-income country in the African region.

Functions for estimating stem diameter and tree age using tree height, crown width and existing stand database information

Abstract

Effects of coastal submarine canyons on tsunami propagation and impact

We analyse the variations produced on tsunami propagation and impact over a straight coastline because of the presence of a submarine canyon incised in the continental margin. For ease of calculation we assume that the shoreline and the shelf edge are parallel and that the incident wave approaches them normally. A total of 512 synthetic scenarios have been computed by combining the bathymetry of a continental margin incised by a parameterised single canyon and the incident tsunami waves. The margin bathymetry, the canyon and the tsunami waves have been generated using mathematical functions (e.g. Gaussian). Canyon parameters analysed are: (i) incision length into the continental shelf, which for a constant shelf width relates directly to the distance from the canyon head to the coast, (ii) canyon width, and (iii) canyon orientation with respect to the shoreline. Tsunami wave parameters considered are period and sign. The COMCOT tsunami model from Cornell University was applied to propagate the waves across the synthetic bathymetric surfaces. Five simulations of tsunami propagation over a non-canyoned margin were also performed for reference. The analysis of the results reveals a strong variation of tsunami arrival times and amplitudes reaching the coastline when a tsunami wave travels over a submarine canyon, with changing maximum height location and alongshore extension. In general, the presence of a submarine canyon lowers the arrival time to the shoreline but prevents wave build-up just over the canyon axis. This leads to a decrease in tsunami amplitude at the coastal stretch located just shoreward of the canyon head, which results in a lower run-up in comparison with a non-canyoned margin. Contrarily, an increased wave build-up occurs on both sides of the canyon head, generating two coastal stretches with an enhanced run-up. These aggravated or reduced tsunami effects are modified with (i) proximity of the canyon tip to the coast, amplifying the wave height, (ii) canyon width, enlarging the areas with lower and higher maximum height wave along the coastline, and (iii) canyon obliquity with respect to the shoreline and shelf edge, increasing wave height shoreward of the leeward flank of the canyon. Moreover, the presence of a submarine canyon near the coast produces a variation of wave energy along the shore, eventually resulting in edge waves shoreward of the canyon head. Edge waves subsequently spread out alongshore reaching significant amplitudes especially when coupling with tsunami secondary waves occurs. Model results have been groundtruthed using the actual bathymetry of Blanes Canyon area in the North Catalan margin. This paper underlines the effects of the presence, morphology and orientation of submarine canyons as a determining factor on tsunami propagation and impact, which could prevail over other effects deriving from coastal configuration.

Improved NYVAC-based vaccine vectors.

While as yet there is no vaccine against HIV/AIDS, the results of the phase III Thai trial (RV144) have been encouraging and suggest that further improvements of the prime/boost vaccine combination of a poxvirus and protein are needed. With this aim, in this investigation we have generated derivatives of the candidate vaccinia virus vaccine vector NYVAC with potentially improved functions. This has been achieved by the re-incorporation into the virus genome of two host range genes, K1L and C7L, in conjunction with the removal of the immunomodulatory viral molecule B19, an antagonist of type I interferon action. These novel virus vectors, referred to as NYVAC-C-KC and NYVAC-C-KC-ΔB19R, have acquired relevant biological characteristics, giving higher levels of antigen expression in infected cells, replication-competency in human keratinocytes and dermal fibroblasts, activation of selective host cell signal transduction pathways, and limited virus spread in tissues. Importantly, these replication-competent viruses have been demonstrated to maintain a highly attenuated phenotype.

Endogenous growth with capital in R&D production functions

[eng] In this paper we claim that capital is as important in the production of ideas as in the production of final goods. Hence, we introduce capital in the production of knowledge and discuss the associated problems arising from the public good nature of knowledge. We show that although population growth can affect economic growth, it is not necessary for growth to arise. We derive both the social planner and the decentralized economy growth rates and show the optimal subsidy that decentralizes it. We also show numerically that the effects of population growth on the market growth rate, the optimal growth rate and the optimal subsidy are small. Besides, we find that physical capital is more important for the production of knowledge than for the production of goods.

Endogenous growth with capital in R&D production functions

[eng] In this paper we claim that capital is as important in the production of ideas as in the production of final goods. Hence, we introduce capital in the production of knowledge and discuss the associated problems arising from the public good nature of knowledge. We show that although population growth can affect economic growth, it is not necessary for growth to arise. We derive both the social planner and the decentralized economy growth rates and show the optimal subsidy that decentralizes it. We also show numerically that the effects of population growth on the market growth rate, the optimal growth rate and the optimal subsidy are small. Besides, we find that physical capital is more important for the production of knowledge than for the production of goods.

Aggregation invariance in general clustering approaches

General clustering deals with weighted objects and fuzzy memberships. We investigate the group- or object-aggregation-invariance properties possessed by the relevant functionals (effective number of groups or objects, centroids, dispersion, mutual object-group information, etc.). The classical squared Euclidean case can be generalized to non-Euclidean distances, as well as to non-linear transformations of the memberships, yielding the c-means clustering algorithm as well as two presumably new procedures, the convex and pairwise convex clustering. Cluster stability and aggregation-invariance of the optimal memberships associated to the various clustering schemes are examined as well.

Biochemical characterization of FANCD2 and FANCM in the Fanconi Anaemia pathway

Abstract : The maintenance of genome stability is a challenge for all living organisms. DNA is regularly subjected to chemical alterations by both endogenous and exogenous DNA damaging agents. If left unrepaired, these lesions will create mutations or lead to chromosomal instability. DNA crosslinking agents probably bring about the most toxic lesions. By linking covalently the two strands of DNA, crosslinking agents will impede essential cellular processes such as replication and transcription. Cells from Fanconi anaemia patients are extremely sensitive to these agents. Fanconi anaemia (FA) is a rare chromosomal instability disorder that leads to developmental defects, pancytopenia and cancer susceptibility. FA is a genetically heterogeneous disease with thirteen complementation groups identified. Proteins encoded by the FA genes work together in the FA pathway. Eight of these proteins form the FA core complex (FANC-A, B, C,E, F, G, L and -M), whose integrity is required to monoubiquitinate FANCD2 and FANCI in response to DNA damage. The hypersensitivity of FA cells to crosslinking agents, which perturb the progression of replication forks, has led to the hypothesis that FA proteins play a crucial role in the response to replication stress. However, at the molecular level, the functions of the FA pathway remain largely unknown. Our efforts were first focused on the characterization of FANCD2, "the key effector of the FA pathway". Using different substrates, we found that in vitro, purified hFANCD2 preferentially binds single strand DNA and double strand DNA extremities. Concomitantly, FANCM was identified as a new component of the FA core complex. Moreover FANCM was shown to have specific branch migration activities and probably a role as a "landing platform" on DNA for the other components of the core complex. By using FANCM mutants carrying deletions within the internal domain, we investigated the role of FANCM as a DNA anchor protein for the core complex. We observed that indeed, a specific part of the internal domain of FANCM interacts with components of the core complex. Finally, in collaboration with Weidong Wang's lab we characterized two new components of the FA pathway: FAAP10 and FAAP16. As a heterodimer these two proteins show affinity for dsDNA, and anneal complementary oligonucleotides in vitro. Moreover these proteins can associate with FANCM via a part of its internal domain. We find that FANCM, FAAP 10 and FAAP 16 can co-exist on the branch point of replication and recombination intermediates, and that FAAP10 and FAAP16 stimulate replication fork reversal by FANCM. These results suggest that FANCM may function as a landing platform for the core complex. After loading on DNA, the core complex can activate FANCD2 through monoubiquitination leading to its recruitment to the site of damage. Since ssDNA and double strand breaks are intermediates that are generated as a consequence of collapsed replication forks, FANCD2 by binding to ds DNA ends and ssDNA could protect such structures from the recombination repair machinery and prevent unscheduled recombination events. Alternatively, FANCD2 could avoid nucleases from gaining access to collapsed forks, preserving the DNA in state that can be used as a starting point for resumption of DNA synthesis. The overall comprehension of the FA pathway is far from been complete. Our results unravel new aspects of Fanconi Anaemia, which hopefully in the near future will address keys questions leading to a better understanding of the fascinating Fanconi Anaemia. Résumé : Le maintien de l'intégrité du génome est fondamentale chez tous les organismes vivants. L'ADN est constamment altéré par des composés aussi bien endogènes qu'exogènes. Si ces altérations ne sont pas réparées, elles peuvent conduire à l'apparition de mutations, ainsi qu'à une instabilité génomique accrue. Les lésions les plus sévères qui peuvent survenir sur l'ADN, sont les pontages inter caténaires. Des agents pontants en liant de façon covalente les deux brins d'ADN, vont empêcher le déroulement normal de processus cellulaires essentiels tels que la réplication ou la transcription. La compréhension des mécanismes permettant à la cellule de tolérer et réparer ces lésions est primordiale, notamment dans le cas des patients atteints de l'anémie de Fanconi qui présentent une très grande sensibilité à ces composés pontants. L'anémie de Fanconi est une maladie génétique rare appartenant à un groupe de pathologies associées à une grande instabilité chromosomique. Les patients atteints de l'anémie de Fanconi présentent des malformations du squelette, une pancytopénie et une forte propension à la survenue de cancer. L'anémie de Fanconi est génétiquement très hétérogène. À ce jour, 13 gènes codant pour 13 protéines FANC différentes ont été identifiés. Huit de ces protéines fonctionnent ensemble au sein d'un complexe (nommé le complexe FANC) ayant pour but de monoubiquitiner FANCD2 et FANCI en réponse à la formation de lésions sur l'ADN. L'extrême sensibilité des cellules de patients atteints de l'anémie de Fanconi à ces agents pontant l'ADN suggère l'implication des protéines FANC dans la réponse cellulaire suite à une stress réplicatif. Cependant, le rôle moléculaire exact de ces protéines demeure encore inconnu. Après purification, nous avons observé que FANCD2 était capable de lier l'ADN simple brin, ainsi que les extrémités d'ADN in vitro. Dans le même temps, FANCM fut identifié comme appartenant au complexe FANC. FANCM est décrit comme une translocase capable de promouvoir le déplacement de point de jonction dans des structures d'ADN spécifiques in vitro. De plus, en se liant à l'ADN, FANCM peut agir comme une plateforme pour les autres protéines FANC, leur permettant ainsi d'être adressées à l'ADN. En créant des protéines FANCM recombinantes ayant des délétions dans le domaine interne, nous avons pu observer que certaines protéines du complexe FANC se fixent à des sites spécifiques sur le domaine interne de FANCM. Enfin, au travers d'une collaboration, nous avons été amenés à caractériser deux nouvelles protéines appartenant au complexe FANC : FAAP 10 et FAAP16. Elles s'associent à FANCM par l'intermédiaire du domaine interne, et forment ainsi un hétérotrimére. La présence de FAAP10 et FAAP16 n'affecte pas la liaison de FANCM à l'ADN, mais semble potentialiser son activité de régression in vitro. FANCM semble donc fonctionner comme une plateforme pour les autres composants du complexe FANC. Ces derniers, une fois liés à l'ADN permettent la monoubiquitination de FANCD2 et son recrutement au site lésé de l'ADN. FANCD2 en se liant de façon préférentielle à l'ADN simple brin et aux extrémités d'ADN qui sont générés lors de l'arrêt et du démantèlement d'une fourche de réplication, pourrait protéger ces même fourches de réplication arrêtées, d'évènements de recombinaison aléatoires. Nos résultats apportent de nouveaux éléments concernant les mécanismes moléculaires de l'anémie de Fanconi. Enfin, l'étude de l'anémie de Fanconi permet aussi de mieux comprendre les mécanismes mis en place par la cellule pour tolérer des lésions survenant lors de la réplication.