The proteostasis network and its decline in ageing

Ageing is a major risk factor for the development of many diseases, prominently including neurodegenerative disorders such as Alzheimer disease and Parkinson disease. A hallmark of many age-related diseases is the dysfunction in protein homeostasis (proteostasis), leading to the accumulation of protein aggregates. In healthy cells, a complex proteostasis network, comprising molecular chaperones and proteolytic machineries and their regulators, operates to ensure the maintenance of proteostasis. These factors coordinate protein synthesis with polypeptide folding, the conservation of protein conformation and protein degradation. However, sustaining proteome balance is a challenging task in the face of various external and endogenous stresses that accumulate during ageing. These stresses lead to the decline of proteostasis network capacity and proteome integrity. The resulting accumulation of misfolded and aggregated proteins affects, in particular, postmitotic cell types such as neurons, manifesting in disease. Recent analyses of proteome-wide changes that occur during ageing inform strategies to improve proteostasis. The possibilities of pharmacological augmentation of the capacity of proteostasis networks hold great promise for delaying the onset of age-related pathologies associated with proteome deterioration and for extending healthspan

Full-field structured-illumination super-resolution X-ray transmission microscopy

Modern transmission X-ray microscopy techniques provide very high resolution at low and medium X-ray energies, but suffer from a limited field-of-view. If sub-micrometre resolution is desired, their field-of-view is typically limited to less than one millimetre. Although the field-of-view increases through combining multiple images from adjacent regions of the specimen, so does the required data acquisition time. Here, we present a method for fast full-field super-resolution transmission microscopy by structured illumination of the specimen. This technique is well-suited even for hard X-ray energies above 30 keV, where efficient optics are hard to obtain. Accordingly, investigation of optically thick specimen becomes possible with our method combining a wide field-of-view spanning multiple millimetres, or even centimetres, with sub-micron resolution and hard X-ray energies

A simplex of bound entangled multipartite qubit states

We construct a simplex for multipartite qubit states of even number n of qubits, which has the same geometry concerning separability, mixedness, kind of entanglement, amount of entanglement and nonlocality as the bipartite qubit states. We derive the entanglement of the class of states which can be described by only three real parameters with the help of a multipartite measure for all discrete systems. We prove that the bounds on this measure are optimal for the whole class of states and that it reveals that the states possess only n-partite entanglement and not e.g. bipartite entanglement. We then show that this n-partite entanglement can be increased by stochastic local operations and classical communication to the purest maximal entangled states. However, pure n-partite entanglement cannot be distilled, consequently all entangled states in the simplex are n-partite bound entangled. We study also Bell inequalities and find the same geometry as for bipartite qubits. Moreover, we show how the (hidden) nonlocality for all n-partite bound entangled states can be revealed.Comment: 11 pages, 4 figures; 2nd version changed considerably and a detailed derivation of the multipartite measure is include

Functional Modules of the Proteostasis Network

Cells invest in an extensive network of factors to maintain protein homeostasis (proteostasis) and prevent the accumulation of potentially toxic protein aggregates. This proteostasis network (PN) comprises the machineries for the biogenesis, folding, conformational maintenance, and degradation of proteins with molecular chaperones as central coordinators. Here, we review recent progress in understanding the modular architecture of the PN in mammalian cells and how it is modified during cell differentiation. We discuss the capacity and limitations of the PN in maintaining proteome integrity in the face of proteotoxic stresses, such as aggregate formation in neurodegenerative diseases. Finally, we outline various pharmacological interventions to ameliorate proteostasis imbalance

Sis1 potentiates the stress response to protein aggregation and elevated temperature

Cells adapt to conditions that compromise protein conformational stability by activating various stress response pathways, but the mechanisms used in sensing misfolded proteins remain unclear. Moreover, aggregates of disease proteins often fail to induce a productive stress response. Here, using a yeast model of polyQ protein aggregation, we identified Sis1, an essential Hsp40 co-chaperone of Hsp70, as a critical sensor of proteotoxic stress. At elevated levels, Sis1 prevented the formation of dense polyQ inclusions and directed soluble polyQ oligomers towards the formation of permeable condensates. Hsp70 accumulated in a liquid-like state within this polyQ meshwork, resulting in a potent activation of the HSF1 dependent stress response. Sis1, and the homologous DnaJB6 in mammalian cells, also regulated the magnitude of the cellular heat stress response, suggesting a general role in sensing protein misfolding. Sis1/DnaJB6 functions as a limiting regulator to enable a dynamic stress response and avoid hypersensitivity to environmental changes. Identifying factors that enable cells to induce a potent stress response to amyloid-like aggregation can provide further insight into the mechanism of stress regulation. Here, the authors express polyglutamine-expanded Huntingtin as a model disease protein in yeast cells and perform a genetic screen for chaperone factors that allow yeast cells to activate a potent stress response. They identify Sis1, an essential Hsp40 co-chaperone of Hsp70, as a critical sensor of proteotoxic stress and further show that both Sis1 and its mammalian homolog DnaJB6 regulate the magnitude of the cellular heat stress response, indicating that this mechanism is conserved.FRAP experiments were performed at the Max Planck Institute of Biochemistry Imaging Core Facility

Work-related correlates of occupational sitting in a diverse sample of employees in Midwest metropolitan cities

The worksite serves as an ideal setting to reduce sedentary time. Yet little research has focused on occupational sitting, and few have considered factors beyond the personal or socio-demographic level. The current study i) examined variation in occupational sitting across different occupations, ii) explored whether worksite level factors (e.g., employer size, worksite supports and policies) may be associated with occupational sitting. Between 2012 and 2013, participants residing in four Missouri metropolitan areas were interviewed via telephone and provided information on socio-demographic characteristics, schedule flexibility, occupation, work related factors, and worksite supports and policies. Occupational sitting was self-reported (daily minutes spent sitting at work), and dichotomized. Occupation-stratified analyses were conducted to identify correlates of occupational sitting using multiple logistic regressions. A total of 1668 participants provided completed data. Those employed in business and office/administrative support spent more daily occupational sitting time (median 330 min) compared to service and blue collar employees (median 30 min). Few worksite supports and policies were sitting specific, yet factors such as having a full-time job, larger employer size, schedule flexibility, and stair prompt signage were associated with occupational sitting. For example, larger employer size was associated with higher occupational sitting in health care, education/professional, and service occupations. Work-related factors, worksite supports and policies are associated with occupational sitting. The pattern of association varies among different occupation groups. This exploratory work adds to the body of research on worksite level correlates of occupational sitting. This may provide information on priority venues for targeting highly sedentary occupation groups

Exploring Co‐Parent Experiences of Sexuality in the First 3 Months after Birth

Introduction Research on postpartum sexuality has focused primarily on mothers, though new findings suggest that relational perceptions may have a strong influence over sexual desire and behavior. Little investigation exists regarding sexuality in partners of postpartum women. Additionally, recent findings point to the importance of a partner's sexuality for postpartum women's perceptions of their own sexuality in this time. Aims The goal of this research was to explore women's partners' sexuality in the early postpartum phase taking into account psychosocial context. Methods Partners (N = 114; 95 men, 18 women, 1 unspecified) of postpartum women completed a retrospective online questionnaire about their sexuality during the 3 months following their youngest child's birth. Main Outcome Measures Primary measures included sexual desire ( S exual D esire I nventory), latency to sexual behavior, and enjoyment and initiation of sexual behavior. Other psychosocial variables were investigated: partners' perceptions of the birth mother's sexual desire, perceptions of the birth experience ( Q uestionnaire M easuring A ttitudes A bout L abor and D elivery), postpartum stress ( P erceived S tress S cale), body image self‐consciousness ( B ody I mage S elf‐ C onsciousness S cale), social support ( M ultidimensional S cale of P erceived S ocial S upport), fatigue, and experiences surrounding breastfeeding. Results Partners reported most frequent engagement in intercourse in the postpartum period, earliest engagement in masturbation, and highest enjoyment of receiving oral sex compared with other sexual activities. Partners' sexual desire was not correlated with the psychosocial variables measured in the study. Findings for partners' sexuality were similar by gender, except for perceptions of social support and likelihood to engage in intercourse. Conclusions This study provided a novel perspective on the study of postpartum sexuality by investigating physical and psychosocial influences on the experiences of partners of parous women. Given parallels between sexuality reported by partners in this study and by birth mothers in past studies, this study provided evidence that sexuality in the postpartum period may be experienced similarly, highlighting the social and relational nature of the postpartum. van Anders SM, Hipp LE, and Kane Low L. Exploring co‐parent experiences of sexuality in the first 3 months after birth. J Sex Med 2013;10:1988–1999.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99697/1/jsm12194.pd

Automated Ecological Assessment of Physical Activity: Advancing Direct Observation.

Technological advances provide opportunities for automating direct observations of physical activity, which allow for continuous monitoring and feedback. This pilot study evaluated the initial validity of computer vision algorithms for ecological assessment of physical activity. The sample comprised 6630 seconds per camera (three cameras in total) of video capturing up to nine participants engaged in sitting, standing, walking, and jogging in an open outdoor space while wearing accelerometers. Computer vision algorithms were developed to assess the number and proportion of people in sedentary, light, moderate, and vigorous activity, and group-based metabolic equivalents of tasks (MET)-minutes. Means and standard deviations (SD) of bias/difference values, and intraclass correlation coefficients (ICC) assessed the criterion validity compared to accelerometry separately for each camera. The number and proportion of participants sedentary and in moderate-to-vigorous physical activity (MVPA) had small biases (within 20% of the criterion mean) and the ICCs were excellent (0.82-0.98). Total MET-minutes were slightly underestimated by 9.3-17.1% and the ICCs were good (0.68-0.79). The standard deviations of the bias estimates were moderate-to-large relative to the means. The computer vision algorithms appeared to have acceptable sample-level validity (i.e., across a sample of time intervals) and are promising for automated ecological assessment of activity in open outdoor settings, but further development and testing is needed before such tools can be used in a diverse range of settings

Latent profile analysis of accelerometer-measured sleep, physical activity, and sedentary time and differences in health characteristics in adult women.

ObjectivesIndependently, physical activity (PA), sedentary behavior (SB), and sleep are related to the development and progression of chronic diseases. Less is known about how rest-activity behaviors cluster within individuals and how rest-activity behavior profiles relate to health. In this study we aimed to investigate if adult women cluster into profiles based on how they accumulate rest-activity behavior (including accelerometer-measured PA, SB, and sleep), and if participant characteristics and health outcomes differ by profile membership.MethodsA convenience sample of 372 women (mean age 55.38 + 10.16) were recruited from four US cities. Participants wore ActiGraph GT3X+ accelerometers on the hip and wrist for a week. Total daily minutes in moderate-to-vigorous PA (MVPA) and percentage of wear-time spent in SB was estimated from the hip device. Total sleep time (hours/minutes) and sleep efficiency (% of in bed time asleep) were estimated from the wrist device. Latent profile analysis (LPA) was performed to identify clusters of participants based on accumulation of the four rest-activity variables. Adjusted ANOVAs were conducted to explore differences in demographic characteristics and health outcomes across profiles.ResultsRest-activity variables clustered to form five behavior profiles: Moderately Active Poor Sleepers (7%), Highly Actives (9%), Inactives (41%), Moderately Actives (28%), and Actives (15%). The Moderately Active Poor Sleepers (profile 1) had the lowest proportion of whites (35% vs 78-91%, p < .001) and college graduates (28% vs 68-90%, p = .004). Health outcomes did not vary significantly across all rest-activity profiles.ConclusionsIn this sample, women clustered within daily rest-activity behavior profiles. Identifying 24-hour behavior profiles can inform intervention population targets and innovative behavioral goals of multiple health behavior interventions

Occupational sitting and weight status in a diverse sample of employees in Midwest metropolitan cities, 2012–2013

INTRODUCTION: Few studies have examined the association between occupational sitting and body mass index (BMI). There is a particular lack of evidence among diverse populations. The objective of this study was to quantify the association between self-reported occupational sitting time and BMI by sex and race, independent of levels of occupational and leisure-time physical activity. METHODS: In 2012 and 2013, participants residing in 4 Missouri metropolitan areas were interviewed via telephone. The interview included questions on sociodemographic characteristics and time spent sitting at work. Multinomial logistic regressions were used to examine the association between occupational sitting and BMI between men and women and between black and white women. RESULTS: Overall 1,891 participants (66.9% women, 29.5% black) provided complete data. Median daily time spent by both men and women in occupational sitting was 180 minutes (interquartile range, 30 to 360 minutes); most participants were overweight (32.3%) or obese (33.6%). After adjusting for potential confounders, we found that black women in 3 categories of sitting time (31–180 minutes, 181–360 minutes, and >360 minutes) were approximately 2.5 times as likely (P for trend, .02) to be obese as black women who reported sitting for 30 minutes or less, independent of occupational and leisure-time physical activity. This association was not seen among white women. No significant associations were found among men. CONCLUSION: Occupational sitting is associated with an increased likelihood of obesity among black women, independent of occupational and leisure-time physical activity. Areas of future research include evaluating associations among various occupations and industries, assessing the association in prospective cohorts, and exploring the feasibility of worksite interventions that target sitting