Multiscale Modeling Approach toward the Prediction of Viscoelastic Properties of Polymers.

We report a multiscale modeling approach to study static and dynamical properties of polymer melts at large time and length scales. We use a bottom-up approach consisting of deriving coarse-grained models from an atomistic description of the polymer melt. We use the iterative Boltzmann inversion (IBI) procedure and a pressure-correction function to map the thermodynamic conditions of the atomistic configurations. The coarse-grained models are incorporated in the dissipative particle dynamics (DPD) method. The thermodynamic, structural, and dynamical properties of the cis-1,4-polybutadiene melt are very well reproduced by the coarse-grained DPD models with a significative computational gain. We complete this study by addressing the challenging question of the investigation of the shear modulus evolution. As expected from experiments, the stress correlation functions show behaviors that are dependent on the molecular weights defining unentangled and weakly entangled polymer melts.

Behavioral and adrenal responses to various stressors in mule ducks from different commercial genetic selection schemes and their respective parental genotypes.

The mule duck, a hybrid produced by crossing a Muscovy drake and a Pekin female, is reported to express inappropriate behavior such as collective avoidance of people, the resulting distress and physical consequences potentially compromising their welfare. The present study was carried out to characterize the responses of mule duck strains from different commercial selection schemes to various stressful conditions and to confirm previous data on the genetic cross effects observed in a specific genotype. Three independent experiments were conducted with ducks from 3 French breeding companies (A, B, and C). Each experiment compared 2 mule genotypes sharing one common parental origin (paternal for ducks from company A or maternal for ducks from companies B and C). Mule duck males from the 2 genotypes and their respective parental genotypes (Pekin and Muscovy) were subjected to a set of social and stressful physiological and behavioral tests. Previously reported differences in genetic cross effects on fear responses between the parental genotypes and the corresponding hybrid were confirmed in these commercial crosses. Both mule duck and Pekin genotypes showed more active physiological and behavioral responses to stress than Muscovy genotypes. The new finding of this study is that mule genotypes appear to be more sensitive to the social environment than both respective parental genotypes. Few differences were observed between the 2 mule genotypes from A and C. On the other hand, several traits of the 2 mule genotypes from B differed. In addition, A and C mule genotypes were characterized by the same adrenal and behavioral traits but contrasting responses. The B mule genotypes were characterized by a different set of behavioral traits, and only 1 of the 2 B mule ducks was characterized by a group of adrenal traits.

Circulating corticosterone reaction to restraint and adrenocorticotropin hormone administration in white leghorns selected for immune response traits.

Corticosterone plasma concentration was measured in a random-bred control line and in 3 White Leghorn chicken lines previously selected over 9 generations for 3 different in vivo immune responses: high antibody response to Newcastle disease virus vaccine 3 wk after vaccination (ND3), high cell-mediated immune response (response to phytohemagglutinin, PHA), and high phagocytic activity measured as carbon clearance (CC). The objective of the study was to estimate if selection on immune response had an effect on the response to stress assessed by measures of corticosterone concentration before and after physical stress or adrenocorticotropin hormone injection and if the effect was dependent on the immune response trait that had been selected for, by joint analyses of immune responses and concentrations. The mean values of plasma corticosterone measures did not differ between lines, indicating that selection for different high immune responses had little effect on response to stress. Within line, however, significant negative correlations (-0.46

Intensity and duration of corticosterone response to stressful situations in Japanese quail divergently selected for tonic immobility.

Two genotypes of Japanese quail have been divergently selected since the 1980s for long (LTI) or short (STI) duration of tonic immobility [Mills, A.D., Faure, J.M., 1991. Divergent selection for duration of tonic immobility and social reinstatement behavior in Japanese quail (Coturnix coturnix japonica) chicks. J. Comp. Psychol. 105(1), 25-38.], an unlearnt catatonic state characteristic of a behavioral fear response ([Jones, R.B., 1986. The tonic immobility reaction of the domestic fowl: a review. World's Poult. Sci. J. 42(1), 82-97.]; [Mills, A.D., Faure, J.M., 1991. Divergent selection for duration of tonic immobility and social reinstatement behavior in Japanese quail (Coturnix coturnix japonica) chicks. J. Comp. Psychol. 105(1), 25-38.]). The results of several behavioral tests conducted in LTI and STI quail have led to the conclusion that LTI quail are more fearful than STI quail [Faure, J.M., Mills, A.D., 1998. Improving the adaptability of animals by selection. In: Grandin, T. (Eds.), Genetics and the behavior of domestic animals. Academic Press, San Diego, pp. 235-264.]). However, few studies to date have focused on the Hypothalamic-Pituitary-Adrenal (HPA) axis response to stressful situations in LTI and STI quail, although the HPA axis is involved in fear responses [Siegel, H.S., 1971. Adrenals, Stress and the Environment. World's Poult. Sci. J. 27, 327-349.]. The corticosterone (CORT) response to various putatively stressful situations was therefore assessed in LTI and STI genotypes of quail in order to investigate their HPA axis reactivity to stress. Repeated induction of TI or 1 min manual restraint induced significant and comparable increases in CORT levels in both genotypes as a TI response. On the other hand, higher CORT responses were found in STI than in LTI quail when the manual restraint period lasted for 2 min or after restraint in a crush cage. Maximum CORT responses and genotype differences were maintained throughout the latter test even when it lasted for 120 min. Investigation of the CORT response to a single TI episode showed that CORT levels at the end of TI were negatively correlated with TI duration. Other experimental contexts consisting of isolation in a familiar or novel environment or the presentation of a novel object induced slight but significant and comparable increases in CORT response in both genotypes, whereas change of cagemates did not. In conclusion, the present findings indicate that differences in HPA axis response are observed between LTI and STI genotypes when quail are submitted to intense stressors, resulting in a high and prolonged CORT response. By contrast, plasma corticosterone concentrations do not differ between STI and LTI quail in response to stressful situations of lower intensity, which evoke responses limited in amplitude and duration. Genetic selection for divergent duration of TI has thus affected the HPA axis response to stress, and LTI and STI quail constitute an interesting model to investigate genetic variability of HPA axis activity in birds. More specifically, these genotypes of quail could be used to investigate the occurrence of functional differences at different levels of the HPA axis in order to explain the present findings.

Characterization of CRF, AVT, and ACTH cDNA and pituitary-adrenal axis function in Japanese quail divergently selected for tonic immobility.

Higher corticosterone (CORT) responses to acute stress have previously been reported in quail selected for short (STI) duration of tonic immobility (TI) than for long TI (LTI), although behavioral studies indicated that LTI quail were more fearful. To investigate adrenal and pituitary function in these quail lines and their possible involvement in the differences in hypothalamic-pituitary-adrenal (HPA) axis reactivity, we measured CORT responses to adrenocorticotropin (1-24 ACTH), corticotropin-releasing factor (CRF), and arginine vasotocin (AVT) after characterizing the nucleotide acid sequences of these peptides in quail. Although maximum adrenal responses, assessed by ACTH challenge, were higher in STI quail, adrenal sensitivity was comparable for the two genotypes. It is therefore unlikely that differences in HPA axis reactivity involved the adrenal level. AVT and ACTH induced comparable CORT responses in both genotypes, whereas those induced by CRF were much lower. AVT is thus more potent than CRF in quail, but the respective maximum pituitary capacity of both genotypes to secrete ACTH was similar, and it is doubtful that the AVT pathway is involved in the difference in HPA axis reactivity between genotypes. On the other hand, the higher CORT responses induced by CRF in STI quail suggest that CRF might be involved in the differences in HPA axis reactivity between LTI and STI genotypes.

Relationship between hypothalamic-pituitary-adrenal axis responsiveness and age, sexual maturity status, and sex in Japanese quail selected for long or short duration of tonic immobility.

The influences of age (4 to 12 wk), sexual maturity status, and sex on hypothalamic-pituitary-adrenal (HPA) axis responsiveness were investigated by measuring changes in peripheral basal levels of corticosterone (B) and responses to 10 min of physical restraint in a crush cage or injection of 1-24 adrenocorticotropic hormone (ACTH) in 2 genotypes of Japanese quail divergently selected for long (LTI) or short (STI) duration of tonic immobility (TI). Although gonad development was more advanced in male STI quail, most birds were still immature at 4 wk of age, but sexual maturity was fully acquired by 6 wk of age in both sexes and genotypes. This change was associated with increases in basal B levels in both genotypes and sexes. On the other hand, HPA axis responsiveness to restraint and adrenal responsiveness to 1-24 ACTH injection remained stable in STI quail, whatever the age. Conversely, significant responses to restraint compared with basal B levels were only observed at 4 and 6 wk of age, and adrenal responsiveness increased with age in LTI quail. Moreover, higher B levels were measured in response to restraint in STI than in LTI quail, whereas similar adrenal responses were measured at 9 and 12 wk of age. We concluded that an increase in basal B levels is associated with the stage of sexual maturity acquired, but it did not affect HPA axis responsiveness or adrenal B response capacity. On the other hand, age affected HPA axis responsiveness and adrenal B response capacity in LTI quail of both sexes but not in STI quail. It is hypothesized that functional HPA axis maturity occurs after 6 wk of age in the LTI genotype, but it is reached by 4 wk of age in the STI genotype. In conclusion, the divergent selection program for TI conducted on quail resulted in changes in HPA responsiveness that probably resulted from differences in development rate and function of the adrenal glands or other upstream structures of the HPA axis.

Daily and photoperiod variations of hypothalamic-pituitary-adrenal axis responsiveness in Japanese quail selected for short or long tonic immobility.

The aims of this study were to investigate the existence of a circadian rhythm of basal corticosterone (B) plasma concentrations in male and female Japanese quail lines divergently selected for long (LTI) or short (STI) duration of tonic immobility (TI) and the possible effects of photoperiod length on corticotropic axis reactivity. Significant peaks in B levels were observed throughout the day in 3 out of the 4 groups used in our experiments. However, B levels remained very low for all groups (< 5.0 ng/mL) and there was no consensus between groups. We therefore have no evidence from our results that basal B levels follow a circadian rhythm in adult STI and LTI quail held under a long photoperiod (16L:8D). We also showed that rearing under a long photoperiod (16L:8D) was associated with higher basal B levels and higher B adrenal response capacity to 1-24 adrenocorticotropic hormone (ACTH) injection in the STI and LTI lines compared with a shorter period (8L:16D). Higher hypothalamic-pituitary-adrenal (HPA) axis responsiveness to restraint in a crush cage was also measured in female quail reared under the long photoperiod, and similar responses were measured under both photoperiods in males. This result suggests that the effects of photoperiod length involve both local and more central mechanisms in the control of HPA axis responsiveness according to sex. On the other hand, we showed that the genetic selection program for TI responses induced greater increases in the B level following restraint in STI quail than in LTI quail of both sexes under both photoperiods, but the B adrenal response capacity was similar for both lines and sexes. Although further investigations on both lines regarding adrenal sensitivity are necessary before being able to conclude definitively, our findings strongly suggest that the differences observed in HPA axis responsiveness to restraint between lines are probably not due to differences in adrenal function itself but may involve upstream structures of the HPA axis.

Does the polymorphism 677C-T of the 5,10-methylenetetrahydrofolate reductase gene contribute to homocysteine-related vascular disease?

Whether the 677C-T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene acts as a risk factor for homocysteine-related vascular disease remains a matter of debate. Testing for the 677C-T nucleotide substitution and assay of plasma homocysteine were carried out simultaneously in 69 controls and 113 vascular disease patients from the Paris area. The variant gene frequency as well as the variant homozygous genotype frequency were very similar in controls and patients. Conversely, plasma homocysteine levels were substantially higher in patients than in controls. A slight interaction between the 677C-T MTHFR polymorphism and homocysteinaemia was observed in the patient group only, while a negative correlation between fasting homocysteine and plasma folate levels was found in all individuals homozygous for the 677C-T MTHFR genotype, irrespective of vascular disease. These data suggest that the 677C-T MTHFR polymorphism is not a major determinant of the vascular disease but contributes to increased plasma homocysteine concentration in conjunction with low plasma folate levels.

Basis sets for transition metals: Optimized outer p functions.

Although the (n + 1)p orbital is unoccupied in transition-metal ground-state configurations which are all nd(x) (n + 1)s(y) , these (n + 1)p functions play a crucial role in the structure of transition metal complexes. As we show here, the usual solution, adding one or more diffuse functions, can be insufficient to create an orbital of the correct energy. The major problem appears to be due to the incorrect placement of the (n + 1)p orbital's node. Even splitting the most diffuse component of the np orbital and adding a second diffuse function does not completely solve this problem. Although one can usually solve this deficiency by further uncontracting of the np function, here we offer a set of properly optimized (n + 1)p functions that offer a more compact and satisfactory solution to the proper placements of the node. We show an example of the common deficiencies seen in typical basis sets, including standard basis sets in GAUSSIAN94, and show that the new optimized (n + 1)p function performs well compared to a fully uncontracted basis set. © 1996 by John Wiley & Sons, Inc.

Phenotype and function of peripheral blood and bone marrow T-cell colonies: identification of DC3-, 4-, 8-autoreactive T cells.

The existence of immature autoreactive T cells has been examined in peripheral blood (PB) and bone marrow (BM) derived T-lymphocyte colonies (TLC) that have previously been shown to be potentially generated from CD3-negative BM-T cells. An extensive phenotypical analysis of total and T-depleted TLC showed that both PB- and BM-derived TLC contained a mean of 5% immature T lymphocytes (ITL), which were negative for the CD3, CD4, and CD8 antigens but displayed the CD2 and CD7 antigens. The only detectable immune functions of these isolated ITL were an allo- and an autoreactivity without cytolytic activity. The self-reactivity of ITL was not detected in bulk non T-depleted TLC cells and seemed to be actively suppressed by autologous mature T cells. In addition, the auto-MLR of ITL was totally inhibited by anti-HLA class II but not by anti-class I monoclonal antibody (MoAb) and only partially by anti-CD4 moAb, whereas the anti-CD3 and anti-CD2 MoAbs gave no inhibition. Once activated, ITL could acquire in culture a mature T cell CD3 + CD4 + phenotype. The CD3-, 4-, 8-auto-reactive T cells present in T colonies could represent pre- or post-thymic cells that have not yet undergo or that have escaped the thymic selection.

Antigen-specific proliferative human T cell clones with specificity for diphtheria toxoid: genetic and molecular restriction by class II antigens.

Human T lymphocyte clones (TLC) specific for diphtheria toxoid (DT) were isolated from a DR6/7 individual by cloning in soft agar in vivo sensitized T lymphocytes. We report here the isolation and characterization of 3 of these clones by studying: (a) the kinetic of activation, (b) the surface phenotypes, (c) the fine specificity for one of the 2 DT chains and (d) the genetic restriction of the proliferative response by the haplotype DR7. Moreover, blocking studies of the proliferative response to DT by various immunochemically characterized anti-HLA-DR monoclonal antibodies indicate that, on the DR7 molecule, more than one Ia determinant may participate in the clonal DT proliferative response. By using human TLC of a defined specificity and well-characterized anti-DR monoclonal antibodies, such studies may help to define the functional repertoire of Ia molecules in man.

Differential inhibition of human antigen-specific T cell clone proliferative responses by distinct monoclonal anti-HLA-DR antibodies.

The inhibition of diphtheria toxoid and varidase-specific T cell clones from a single DR 6/7 donor by eight distinct monoclonal anti-HLA-DR antibodies was tested in proliferative assays. These moAb were selected because they had been previously defined for their ability: 1) to react with Ia molecules; 2) to recognize similar or different epitopes; 3) to share or not share idiotypic specificities. Our results show a distinct inhibition pattern for each clone tested. Furthermore, the various moAb could be classified into three groups according to their inhibitory effect on T cell proliferation. These data suggest: a) an epitopic restriction by class II antigens of antigen-specific human T cell clone proliferation; and b) the recognition of functional epitopes on the human Ia-like antigens by some but not all moAb studied.

[Prognostic value of the study of lymphocytic volumes in chronic lymphocytic leukemia (author's transl)]. / Valeur pronostique de l'étude des volumes lymphocytaires dans la leucémie lymphoïde chronique.

The modal volume of peripheral blood lymphocytes from 23 patients with chronic lymphoid leukemia (CLL) was measured by a Coulter ZBI linked to a channalyzer C 1000, varied from 140 to 262 mu3. A statistical correlation between the modal volume and anatomo-clinical forms of the disease was determined: a modal volume below 190 mu3 was statistically found among early forms while a volume over this threshold corresponded to advanced forms. Since Sipe et al. postulated that cell volume might be relayed to the cell kinetics, we attempted to determine the volume distribution law of lymphocytes from 12 CLL cases by applying the chi-square distance test. The best adjustment was observed with the two log-normal populations model, but this adjustment was acceptable for only five cases over twelve. The instability in the determination of the percentage of the second population made it impossible + relate it with the proliferative cell fraction. Moreover, this model did not provide more significant information than the single modal volume.

Computer analysis of platelet volumes.

A Coulter ZB was used to measure electronically the size of circulating platelets collected from normal subjects. EDTA or ACD were used for collection. Three mathematical models of volume histograms were tested. The lognormal law model is clearly unacceptable if all particles are used, but is applicable in the particle range of 3-15 mu 3. The model of a mixture of two lognormal populations closely approximates observed volume distribution. The model of three lognormal populations also approximates well when the largest volume population is divided into two subpopulations. The contribution of these results to an understanding of heterogeneity in platelet size is discussed.

Biochemical and histological analysis of bone marrow collagen in myelofibrosis.

Total protein, collagen (hydroxyproline) and glycoproteins (hexosamine) content of control and myelofibrosis (MF) bone marrow samples was determined using a sequential extraction procedure. MF marrow extracts contained higher amounts of collagen than control extracts. The collagen content appeared to increase with the duration of the disease. In more recent MF cases (less than 2 years) at least 60% of the total collagen was extracted in 0.5 M NaCl. this proportion decreases to 33% in older cases (greater than 4 years), indicating a progressive insolubilization (crosslinking) of collagen. The hexosamine content of the extracts decreased in MF as compared to controls reflecting a decrease in glycosaminoglycans (and possibly of structural glycoproteins). The reticulin content of the same bone marrows was estimated by a quantitative morphometric procedure. There was a positive correlation between the morphometrically estimated reticulin surface and the total hydroxyproline content of the marrow samples. The slopes of the least square lines correlating increase of reticulin surface to hydroxyproline content were, however, significantly different in control and MF marrows, indicating a 44% higher increase in histochemically detectable reticulin per unit increase in hydroxyproline content than in the control marrows. This result may indicate a more efficient fibrogenetic process in MF marrow than in normal bone marrow. The above results confirm the collagenous nature of the fibrous reticulin like material deposited in MR marrows and suggests a correlation between the progression of the disease and the rate of synthesis and deposition of collagen fibres.