Theory and simulation of short-range models of globular protein solutions

We report theoretical and simulation studies of phase coexistence in model globular protein solutions, based on short-range, central, pair potential representations of the interaction among macro-particles. After reviewing our previous investigations of hard-core Yukawa and generalised Lennard-Jones potentials, we report more recent results obtained within a DLVO-like description of lysozyme solutions in water and added salt. We show that a one-parameter fit of this model based on Static Light Scattering and Self-Interaction Chromatography data in the dilute protein regime, yields demixing and crystallization curves in good agreement with experimental protein-rich/protein-poor and solubility envelopes. The dependence of cloud and solubility points temperature of the model on the ionic strength is also investigated. Our findings highlight the minimal assumptions on the properties of the microscopic interaction sufficient for a satisfactory reproduction of the phase diagram topology of globular protein solutions.Comment: 17 pages, 8 figures, Proc. of Conference "Structural Arrest Transitions in Colloidal Systems with Short-Range Attractions", Messina (ITALY) 17-20 December 200

Do diurnal cortisol levels mediate the association between sleep disturbances and cognitive impairment?

Previous research found an association between sleep disturbances and cognitive deficits on the one hand, and between increased cortisol levels and poor cognitive performance on the other hand. We hypothesized that cortisol may, at least partially, mediate the link between sleep disturbances and cognitive impairment (CI). We analyzed data from 440 nondemented subjects aged ≥65 years (72.4 ± 4.5 years old, 55.7% women) participating at the population-based CoLaus/PsyCoLaus study, who underwent cognitive evaluation, complete polysomnography and cortisol measures during the day. Subjects with CI (N = 207, 47.05% of the sample) had lower sleep efficiency, less deep sleep (stage N3) and rapid eye movement sleep, and higher apnea/hypopnea index and oxygen desaturation index. After adjustment for possible confounders, oxygen desaturation index (≥4% and ≥6% per hour of sleep) were significantly associated with impaired cognitive performance. The results of Sobel's test for mediation using the regressions between the sleep-related variables and cortisol values, and between the cortisol and the Clinical Dementia Rating score were not significant (all p > 0.05). Our data suggest that sleep-disordered breathing is associated with CI, but that this association is not mediated by increased diurnal cortisol levels

MutLα heterodimers modify the molecular phenotype of Friedreich ataxia

This article has been made available through the Brunel Open Access Publishing Fund.Background: Friedreich ataxia (FRDA), the most common autosomal recessive ataxia disorder, is caused by a dynamic GAA repeat expansion mutation within intron 1 of FXN gene, resulting in down-regulation of frataxin expression. Studies of cell and mouse models have revealed a role for the mismatch repair (MMR) MutS-heterodimer complexes and the PMS2 component of the MutLα complex in the dynamics of intergenerational and somatic GAA repeat expansions: MSH2, MSH3 and MSH6 promote GAA repeat expansions, while PMS2 inhibits GAA repeat expansions. Methodology/Principal Findings: To determine the potential role of the other component of the MutLα complex, MLH1, in GAA repeat instability in FRDA, we have analyzed intergenerational and somatic GAA repeat expansions from FXN transgenic mice that have been crossed with Mlh1 deficient mice. We find that loss of Mlh1 activity reduces both intergenerational and somatic GAA repeat expansions. However, we also find that loss of either Mlh1 or Pms2 reduces FXN transcription, suggesting different mechanisms of action for Mlh1 and Pms2 on GAA repeat expansion dynamics and regulation of FXN transcription. Conclusions/Significance: Both MutLα components, PMS2 and MLH1, have now been shown to modify the molecular phenotype of FRDA. We propose that upregulation of MLH1 or PMS2 could be potential FRDA therapeutic approaches to increase FXN transcription. © 2014 Ezzatizadeh et al.This article has been made available through the Brunel Open Access Publishing Fund

Developmental expression of orphan g protein-coupled receptor 50 in the mouse brain

[Image: see text] Mental disorders have a complex etiology resulting from interactions between multiple genetic risk factors and stressful life events. Orphan G protein-coupled receptor 50 (GPR50) has been identified as a genetic risk factor for bipolar disorder and major depression in women, and there is additional genetic and functional evidence linking GPR50 to neurite outgrowth, lipid metabolism, and adaptive thermogenesis and torpor. However, in the absence of a ligand, a specific function has not been identified. Adult GPR50 expression has previously been reported in brain regions controlling the HPA axis, but its developmental expression is unknown. In this study, we performed extensive expression analysis of GPR50 and three protein interactors using rt-PCR and immunohistochemistry in the developing and adult mouse brain. Gpr50 is expressed at embryonic day 13 (E13), peaks at E18, and is predominantly expressed by neurons. Additionally we identified novel regions of Gpr50 expression, including brain stem nuclei involved in neurotransmitter signaling: the locus coeruleus, substantia nigra, and raphe nuclei, as well as nuclei involved in metabolic homeostasis. Gpr50 colocalizes with yeast-two-hybrid interactors Nogo-A, Abca2, and Cdh8 in the hypothalamus, amygdala, cortex, and selected brain stem nuclei at E18 and in the adult. With this study, we identify a link between GPR50 and neurotransmitter signaling and strengthen a likely role in stress response and energy homeostasis

Exploring recruitment, willingness to participate, and retention of low-SES women in stress and depression prevention

Contains fulltext : 90907.pdf (publisher's version ) (Open Access)Background Recruitment, willingness to participate, and retention in interventions are indispensable for successful prevention. This study investigated the effectiveness of different strategies for recruiting and retaining low-SES women in depression prevention, and explored which sociodemographic characteristics and risk status factors within this specific target group are associated with successful recruitment and retention. Methods The process of recruitment, willingness to participate, and retention was structurally mapped and explored. Differences between women who dropped out and those who adhered to the subsequent stages of the recruitment and retention process were investigated. The potential of several referral strategies was also studied, with specific attention paid to the use of GP databases. Results As part of the recruitment process, 12.1% of the target population completed a telephone screening. The most successful referral strategy was the use of patient databases from GPs working in disadvantaged neighborhoods. Older age and more severe complaints were particularly associated with greater willingness to participate and with retention. Conclusions Low-SES women can be recruited and retained in public health interventions through tailored strategies. The integration of mental health screening within primary care might help to embed preventive interventions in low-SES communities.8 p

Mental distress in the general population in Zambia: Impact of HIV and social factors

<p>Abstract</p> <p>Background</p> <p>Population level data on mental health from Africa are limited, but available data indicate mental problems to represent a substantial public health problem. The negative impact of HIV on mental health suggests that this could particularly be the case in high prevalence populations. We examined the prevalence of mental distress, distribution patterns and the ways HIV might influence mental health among men and women in a general population.</p> <p>Methods</p> <p>The relationship between HIV infection and mental distress was explored using a sample of 4466 participants in a population-based HIV survey conducted in selected rural and urban communities in Zambia in 2003. The Self-reporting questionnaire-10 (SRQ-10) was used to assess global mental distress. Weights were assigned to the SRQ-10 responses based on DSM IV criteria for depression and a cut off point set at 7/20 for probable cases of mental distress. A structural equation modeling (SEM) was established to assess the structural relationship between HIV infection and mental distress in the model, with maximum likelihood ratio as the method of estimation.</p> <p>Results</p> <p>The HIV prevalence was 13.6% vs. 18% in the rural and urban populations, respectively. The prevalence of mental distress was substantially higher among women than men and among groups with low educational attainment vs. high. The results of the SEM showed a close fit with the data. The final model revealed that self-rated health and self perceived HIV risk and worry of being HIV infected were important mediators between underlying factors, HIV infection and mental distress. The effect of HIV infection on mental distress was both direct and indirect, but was particularly strong through the indirect effects of health ratings and self perceived risk and worry of HIV infection.</p> <p>Conclusion</p> <p>These findings suggest a strong effect of HIV infection on mental distress. In this population where few knew their HIV status, this effect was mediated through self-perceptions of health status, found to capture changes in health perceptions related to HIV, and self-perceived risk and worry of actually being HIV infected.</p

Spatial Extent of Charge Repulsion Regulates Assembly Pathways for Lysozyme Amyloid Fibrils

Formation of large protein fibrils with a characteristic cross β-sheet architecture is the key indicator for a wide variety of systemic and neurodegenerative amyloid diseases. Recent experiments have strongly implicated oligomeric intermediates, transiently formed during fibril assembly, as critical contributors to cellular toxicity in amyloid diseases. At the same time, amyloid fibril assembly can proceed along different assembly pathways that might or might not involve such oligomeric intermediates. Elucidating the mechanisms that determine whether fibril formation proceeds along non-oligomeric or oligomeric pathways, therefore, is important not just for understanding amyloid fibril assembly at the molecular level but also for developing new targets for intervening with fibril formation. We have investigated fibril formation by hen egg white lysozyme, an enzyme for which human variants underlie non-neuropathic amyloidosis. Using a combination of static and dynamic light scattering, atomic force microscopy and circular dichroism, we find that amyloidogenic lysozyme monomers switch between three different assembly pathways: from monomeric to oligomeric fibril assembly and, eventually, disordered precipitation as the ionic strength of the solution increases. Fibril assembly only occurred under conditions of net repulsion among the amyloidogenic monomers while net attraction caused precipitation. The transition from monomeric to oligomeric fibril assembly, in turn, occurred as salt-mediated charge screening reduced repulsion among individual charged residues on the same monomer. We suggest a model of amyloid fibril formation in which repulsive charge interactions are a prerequisite for ordered fibril assembly. Furthermore, the spatial extent of non-specific charge screening selects between monomeric and oligomeric assembly pathways by affecting which subset of denatured states can form suitable intermolecular bonds and by altering the energetic and entropic requirements for the initial intermediates emerging along the monomeric vs. oligomeric assembly path

Psychosocial Stress Over the Lifespan, Psychological Factors, and Cardiometabolic Risk in the Community.

The complex relationship between psychosocial stress over the lifetime, psychological factors, and cardiometabolic risk is still poorly understood. Accordingly, our aims were (1) to independently assess the associations between childhood adversity, life-event stress in remote (earlier than the last 5 years), and recent adulthood and cardiometabolic risk, and (2) to determine the role of psychological factors including personality, coping, and depression in these associations. The sample included 2674 adults, aged 35 to 66 years, randomly selected from urban area. Participants underwent a physical examination including the assessment of obesity markers, blood pressure, and blood lipid and glucose levels. Stress during adulthood was determined using the severity scores of 52 stressful life events. Information on adverse childhood experiences and major depressive disorders was collected using semistructured interviews, whereas personality traits and coping mechanisms were evaluated through questionnaires. Both childhood adversity and stress in remote adulthood were associated with elevated body mass index (β [95% confidence interval {CI}] = 0.249 [0.029 to 0.468]; 0.020 [0.006 to 0.034]), waist circumference (β [95% CI] = 0.061 [0.024 to 0.099]; 0.08 [0.04 to 0.11]), and the global cardiometabolic risk score (β [95% CI] = 0.278 [0.017 to 0.540]; 0.017 [0.001 to 0.033]) after adjustment for sociodemographic, lifestyle, and psychological factors. In addition, childhood adversity was associated with low high density lipoprotein levels (β [95% CI] = -0.021 [-0.042 to 0.000]), as well as increased fat mass and systolic blood pressure levels (β [95% CI] = 0.506 [0.165 to 0.846]; 0.952 [0.165 to 1.740]) and stress in remote adulthood with apolipoprotein B levels (β [95% CI] = 0.607 [0.312 to 0.901]). Psychological factors did not account for these associations and were not effect modifiers. Our data demonstrate that psychosocial stress during childhood and remote adulthood favor adiposity and abnormal lipid metabolism

The relationship between basal and acute HPA axis activity and aggressive behavior in adults

The hypothalamic–pituitary–adrenal (HPA) axis seems to play a major role in the development, elicitation, and enhancement of aggressive behavior in animals. Increasing evidence suggests that this is also true for humans. However, most human research on the role of the HPA axis in aggression has been focusing on highly aggressive children and adolescent clinical samples. Here, we report on a study of the role of basal and acute HPA axis activity in a sample of 20 healthy male and female adults. We used the Taylor Aggression Paradigm to induce and measure aggression. We assessed the cortisol awakening response as a trait measure of basal HPA axis activity. Salivary free cortisol measures for the cortisol awakening response were obtained on three consecutive weekdays immediately following awakening and 30, 45, and 60 min after. Half of the subjects were provoked with the Taylor Aggression Paradigm to behave aggressively; the other half was not provoked. Acute HPA axis activity was measured four times, once before and three times after the induction of aggression. Basal cortisol levels were significantly and negatively related to aggressive behavior in the provoked group and explained 67% of the behavioral variance. Cortisol levels following the induction of aggression were significantly higher in the provoked group when baseline levels were taken into account. The data implicate that the HPA axis is not only relevant to the expression of aggressive behavior in clinical groups, but also to a large extent in healthy ones

The interaction of Pcf11 and Clp1 is needed for mRNA 3′-end formation and is modulated by amino acids in the ATP-binding site

Polyadenylation of eukaryotic mRNAs contributes to stability, transport and translation, and is catalyzed by a large complex of conserved proteins. The Pcf11 subunit of the yeast CF IA factor functions as a scaffold for the processing machinery during the termination and polyadenylation of transcripts. Its partner, Clp1, is needed for mRNA processing, but its precise molecular role has remained enigmatic. We show that Clp1 interacts with the Cleavage–Polyadenylation Factor (CPF) through its N-terminal and central domains, and thus provides cross-factor connections within the processing complex. Clp1 is known to bind ATP, consistent with the reported RNA kinase activity of human Clp1. However, substitution of conserved amino acids in the ATP-binding site did not affect cell growth, suggesting that the essential function of yeast Clp1 does not involve ATP hydrolysis. Surprisingly, non-viable mutations predicted to displace ATP did not affect ATP binding but disturbed the Clp1–Pcf11 interaction. In support of the importance of this interaction, a mutation in Pcf11 that disrupts the Clp1 contact caused defects in growth, 3′-end processing and transcription termination. These results define Clp1 as a bridge between CF IA and CPF and indicate that the Clp1–Pcf11 interaction is modulated by amino acids in the conserved ATP-binding site of Clp1