Dynamic Diagnosis of Familial Prion Diseases Supports the β2-α2 Loop as a Universal Interference Target

[Background] Mutations in the cellular prion protein associated to familial prion disorders severely increase the likelihood of its misfolding into pathogenic conformers. Despite their postulation as incompatible elements with the native fold, these mutations rarely modify the native state structure. However they variably have impact on the thermodynamic stability and metabolism of PrPC and on the properties of PrPSc aggregates. To investigate whether the pathogenic mutations affect the dynamic properties of the HuPrP(125-229) α-fold and find possible common patterns of effects that could help in prophylaxis we performed a dynamic diagnosis of ten point substitutions.[Methodology/Principal Findings] Using all-atom molecular dynamics simulations and novel analytical tools we have explored the effect of D178N, V180I, T183A, T188K, E196K, F198S, E200K, R208H, V210I and E211Q mutations on the dynamics of HuPrP(125-228) α-fold. We have found that while preserving the native state, all mutations produce dynamic changes which perturb the coordination of the α2-α3 hairpin to the rest of the molecule and cause the reorganization of the patches for intermolecular recognition, as the disappearance of those for conversion inhibitors and the emergence of an interaction site at the β2-α2 loop region.[Conclusions/Significance] Our results suggest that pathogenic mutations share a common pattern of dynamical alterations that converge to the conversion of the β2-α2 loop into an interacting region that can be used as target for interference treatments in genetic diseases.This work was supported in parts by grants BFU2009-07971 from the MICINN (MG), FundaciÃ3n Cien (MG); Fondazione Cariplo (GC) and AIRC (GC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.Peer reviewe

Association between overweight, obesity and self-perceived job insecurity in German employees

<p>Abstract</p> <p>Background</p> <p>Recent studies have shown an association between job insecurity and morbidity as well as mortality, however until now, knowledge about a potential association between job insecurity and overweight or obesity has been lacking.</p> <p>Methods</p> <p>In order to identify a possible association between job insecurity and overweight or obesity, we analysed data from the German Socioeconomic Panel (GSOEP) 2004/2005, a longitudinal study of private households in Germany. In this representative cohort of the German adult population, living and working conditions were observed. Data on Body Mass Index (BMI) and self-perceived probability of job loss within the next 2 years were available for 10,747 adults either employed or attending training programs.</p> <p>Results</p> <p>We identified 5,216 (49%) individuals as being overweight (BMI > 25 kg/m²) and 1,358(13%) individuals as being obese (BMI > 30 kg/m²). A total of 5,941 (55%) participants reported having concerns regarding job insecurity. In the multivariate analysis - after adjustment for relevant confounders - a statistically significant association between obesity and job insecurity (100% probability for losing the job in the following two years) could be observed with an adjusted odds ratio of 2.55 (95% confidence interval: 1.09-5.96).</p> <p>Conclusions</p> <p>Because of these results, we were able to conclude that overweight and obese persons perceive job insecurity more often than their normal weight counterparts in Germany and that the concurrence of obesity and job insecurity might lead employees into a vicious cycle. Further research with an emphasis on the occupational setting might be necessary in order to establish useful preventive programmes at the workplace.</p

Virtual Reality and 3D Imaging to Support Collaborative Decision Making for Adaptation of Long-Life Assets

European companies of today are involved in many stages of the product life cycle. There is a trend towards the view of their business as a complex industrial product-service system (IPSS). This trend shifts the business focus from a traditional product oriented one to a function oriented one. With the function in focus, the seller shares the responsibility of for example maintenance of the product with the buyer. As such IPSS has been praised for supporting sustainable practices. This shift in focus also promotes longevity of products and promotes life extending work on the products such as adaptation and upgrades. Staying competitive requires continuous improvement of manufacturing and services to make them more flexible and adaptive to external changes. The adaptation itself needs to be performed efficiently without disrupting ongoing operations and needs to result in an acceptable after state. Virtual planning models are a key technology to enable planning and design of the future operations in parallel with ongoing operations. This chapter presents an approach to combine digitalization and virtual reality (VR) technologies to create the next generation of virtual planning environments. Through incorporating digitalization techniques such as 3D imaging, the models will reach a new level of fidelity and realism which in turn makes them accessible to a broader group of users and stakeholders. Increased accessibility facilitates a collaborative decision making process that invites and includes cross functional teams. Through such involvement, a broader range of experts, their skills, operational and tacit knowledge can be leveraged towards better planning of the upgrade process. This promises to shorte

Selective Cholinergic Depletion in Medial Septum Leads to Impaired Long Term Potentiation and Glutamatergic Synaptic Currents in the Hippocampus

Cholinergic depletion in the medial septum (MS) is associated with impaired hippocampal-dependent learning and memory. Here we investigated whether long term potentiation (LTP) and synaptic currents, mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the CA1 hippocampal region, are affected following cholinergic lesions of the MS. Stereotaxic intra-medioseptal infusions of a selective immunotoxin, 192-saporin, against cholinergic neurons or sterile saline were made in adult rats. Four days after infusions, hippocampal slices were made and LTP, whole cell, and single channel (AMPA or NMDA receptor) currents were recorded. Results demonstrated impairment in the induction and expression of LTP in lesioned rats. Lesioned rats also showed decreases in synaptic currents from CA1 pyramidal cells and synaptosomal single channels of AMPA and NMDA receptors. Our results suggest that MS cholinergic afferents modulate LTP and glutamatergic currents in the CA1 region of the hippocampus, providing a potential synaptic mechanism for the learning and memory deficits observed in the rodent model of selective MS cholinergic lesioning

Vitalism in contemporary chiropractic: a help or a hinderance?

Background: Chiropractic emerged in 1895 and was promoted as a viable health care substitute in direct competition with the medical profession. This was an era when there was a belief that one cause and one cure for all disease would be discovered. The chiropractic version was a theory that most diseases were caused by subluxated (slightly displaced) vertebrae interfering with “nerve vibrations” (a supernatural, vital force) and could be cured by adjusting (repositioning) vertebrae, thereby removing the interference with the body’s inherent capacity to heal. DD Palmer, the originator of chiropractic, established chiropractic based on vitalistic principles. Anecdotally, the authors have observed that many chiropractors who overtly claim to be “vitalists” cannot define the term. Therefore, we sought the origins of vitalism and to examine its effects on chiropractic today. Discussion: Vitalism arose out of human curiosity around the biggest questions: Where do we come from? What is life? For some, life was derived from an unknown and unknowable vital force. For others, a vital force was a placeholder, a piece of knowledge not yet grasped but attainable. Developments in science have demonstrated there is no longer a need to invoke vitalistic entities as either explanations or hypotheses for biological phenomena. Nevertheless, vitalism remains within chiropractic. In this examination of vitalism within chiropractic we explore the history of vitalism, vitalism within chiropractic and whether a vitalistic ideology is compatible with the legal and ethical requirements for registered health care professionals such as chiropractors. Conclusion: Vitalism has had many meanings throughout the centuries of recorded history. Though only vaguely defined by chiropractors, vitalism, as a representation of supernatural force and therefore an untestable hypothesis, sits at the heart of the divisions within chiropractic and acts as an impediment to chiropractic legitimacy, cultural authority and integration into mainstream health care

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Gender differences in the association of perceived social support and social network with self-rated health status among older adults: a population-based study in Brazil

BACKGROUND: Older adults are more likely to live alone, because they may have been predeceased by their spouse and friends. Social interaction could also be reduced in this age group due by limited mobility caused by chronic conditions. Therefore, aging is frequently accompanied by reduced social support, which might affect health status. Little is known about the role of gender in the relationship between social support and health in older adults. Hence, the present study tests the hypothesis that gender differences exist in the relationship between perceived social support, social network, and self-rated health (SRH) among older adults. METHODS: A cross-sectional study using two-stage probabilistic sampling recruited 3,649 individuals aged 60 years and above. Data were collected during the national influenza vaccination campaign in Rio de Janeiro, Brazil, in 2006. Individual interviews collected information on SRH, perceived social support, social network, and other covariates. Multivariate logistic regression analyses using nested models were conducted separately for males and females. Independent variables were organised into six blocks: (1) perceived social support and social network, (2) age group, (3) socioeconomic characteristics, (4) health-related behaviours, (5) use of health care services, (6) functional status measures and somatic health problems. RESULTS: Older men who did not participate in group activities were more likely to report poor SRH compared to those who did, (OR = 1.63; 95% CI = 1.16–2.30). Low perceived social support predicted the probability of poor SRH in women (OR = 1.64; 95% CI = 1.16–2.34). Poor SRH was associated with low age, low income, not working, poor functional capacity, and depression in both men and women. More somatic health problems were associated with poor SRH in women. CONCLUSIONS: The association between social interactions and SRH varies between genders. Low social network involvement is associated with poor SRH in older men, whereas low perceived social support is associated with poor SRH in older women. The hypothesis that the relationship of perceived social support and social networks to SRH differs according to gender has been confirmed