A [4Fe-4S]-Fe(CO)(CN)-L-cysteine intermediate is the first organometallic precursor in [FeFe] hydrogenase H-cluster bioassembly.

Biosynthesis of the [FeFe] hydrogenase active site (the 'H-cluster') requires the interplay of multiple proteins and small molecules. Among them, the radical S-adenosylmethionine enzyme HydG, a tyrosine lyase, has been proposed to generate a complex that contains an Fe(CO)2(CN) moiety that is eventually incorporated into the H-cluster. Here we describe the characterization of an intermediate in the HydG reaction: a [4Fe-4S][(Cys)Fe(CO)(CN)] species, 'Complex A', in which a CO, a CN- and a cysteine (Cys) molecule bind to the unique 'dangler' Fe site of the auxiliary [5Fe-4S] cluster of HydG. The identification of this intermediate-the first organometallic precursor to the H-cluster-validates the previously hypothesized HydG reaction cycle and provides a basis for elucidating the biosynthetic origin of other moieties of the H-cluster

Comparing the immune response to a novel intranasal nanoparticle PLGA vaccine and a commercial BPI3V vaccine in dairy calves

peer-reviewedBackground There is a need to improve vaccination against respiratory pathogens in calves by stimulation of local immunity at the site of pathogen entry at an early stage in life. Ideally such a vaccine preparation would not be inhibited by the maternally derived antibodies. Additionally, localized immune response at the site of infection is also crucial to control infection at the site of entry of virus. The present study investigated the response to an intranasal bovine parainfluenza 3 virus (BPI3V) antigen preparation encapsulated in PLGA (poly dl-lactic-co-glycolide) nanoparticles in the presence of pre-existing anti-BPI3V antibodies in young calves and comparing it to a commercially available BPI3V respiratory vaccine. Results There was a significant (P < 0.05) increase in BPI3V-specific IgA in the nasal mucus of the BPI3V nanoparticle vaccine group alone. Following administration of the nanoparticle vaccine an early immune response was induced that continued to grow until the end of study and was not observed in the other treatment groups. Virus specific serum IgG response to both the nanoparticle vaccine and commercial live attenuated vaccine showed a significant (P < 0.05) rise over the period of study. However, the cell mediated immune response observed didn’t show any significant rise in any of the treatment groups. Conclusion Calves administered the intranasal nanoparticle vaccine induced significantly greater mucosal IgA responses, compared to the other treatment groups. This suggests an enhanced, sustained mucosal-based immunological response to the BPI3V nanoparticle vaccine in the face of pre-existing antibodies to BPI3V, which are encouraging and potentially useful characteristics of a candidate vaccine. However, ability of nanoparticle vaccine in eliciting cell mediated immune response needs further investigation. More sustained local mucosal immunity induced by nanoparticle vaccine has obvious potential if it translates into enhanced protective immunity in the face of virus outbreak

Emergent complex neural dynamics

A large repertoire of spatiotemporal activity patterns in the brain is the basis for adaptive behaviour. Understanding the mechanism by which the brain's hundred billion neurons and hundred trillion synapses manage to produce such a range of cortical configurations in a flexible manner remains a fundamental problem in neuroscience. One plausible solution is the involvement of universal mechanisms of emergent complex phenomena evident in dynamical systems poised near a critical point of a second-order phase transition. We review recent theoretical and empirical results supporting the notion that the brain is naturally poised near criticality, as well as its implications for better understanding of the brain

Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden

Abstract Background It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection. Results Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember&#8482;, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced. Conclusions Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.http://deepblue.lib.umich.edu/bitstream/2027.42/78314/1/1750-1326-5-45.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/2/1750-1326-5-45.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/3/1750-1326-5-45-S1.PDFPeer Reviewe

Tuning of Human Modulation Filters Is Carrier-Frequency Dependent

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Fluid use in mountain bikers - self-reported practices

Background and objectives. Little is known of the fluid replacement habits of participants in mountain bike (MTB) endurance events. This survey set out to determine the current perceptions and practices of this group of endurance athletes. Method. Four hundred and twelve participants in the 3- day 2006 Sani2C (MTB) race completed questionnaires that elicited information regarding their regular fluid intake practices during competitive MTB endurance events. This included their general approach to fluid replacement, their fluid intake practices (type, amount and frequency), urine output and hydration status. Results. While 70% (N = 290) reported that they based their fluid intake practices on personal past experiences, less than half the group (N = 177, 43%) were aware of official sport-specific guidelines. Although 86% (N = 354) reported making use of commercially available sport-specific drinks, consumption of water alone was reported by 34% of respondents (N = 140). The majority (N = 225, 55%) of the mountain bikers reported drinking every 16 - 30 minutes during an endurance ride, while 35% (N = 144) reported drinking every 0 - 15 minutes. Fifty-three per cent (N = 182) of the male respondents and 45% (N = 23) of female respondents reported a routine intake of &#8805; 750 ml per hour during endurance rides. This included 2 women who reported regular intakes of between 1 500 and 2 000 ml/hr. Only 7 (2%) reported receiving medical care for dehydration following their participation in previous MTB rides. Conclusions. This survey indicates that although more than half of the mountain bikers did not acknowledge specific awareness of the official fluid replacement guidelines, over 80% reported drinking regularly during a race, and 52% (N = 212) reported a usual intake of &#8805; 750 ml/hr during endurance races. Until scientific studies have carefully examined the hydration status and fluid replacement needs of mountain bikers, MTB cyclists are cautioned against the practice of over-hydrating. South African Journal of Sports Medicine Vol. 19 (2) 2007: pp. 52-5

Intangible assets and investments at the sector level : empirical evidence for Germany

This paper investigates the role intangible capital plays for economic growth in different sectors in Germany. It consists of two major parts. In the first part, we aim at measuring investment in intangibles at the sector level. We shed light on differences across sectors but also compare these figures with investment in physical capital and with investment in intangibles in the UK as European benchmark. The second part explores the role of intangible assets for stimulating growth at the sector level by performing growth accounting analyses. We find that German firms have boosted investments in intangible capital from 1995-2006 by 30%. Furthermore, results reveal differences in the investment patterns among the UK and Germany. In nearly all sectors investments in design and computerized information are larger in the UK. In contrast, German firms invest a higher proportion of gross output in R&D in all sectors, and advertising is also more common except for the sector trade & transport. Intangible assets have stimulated labour productivity growth in all sectors. The contribution varies between 0.17 (construction) and 0.59 (manufacturing) percentage points. In manufacturing, financial and business services innovative property capital is the most influential type of intangible capital for labour productivity, followed by economic competencies and computerized information. In all other sectors, economic competencies play the most prominent role for labour productivity growth

Postrace upper respiratory tract ‘infections' in ultramarathoners — infection, allergy or inflammation?

Despite more than 20 years of research into mechanisms which could result in the increased predisposition of athletes to ‘infection' incidence following excessive and prolonged exercise, definitive explanations are not yet available. A strong temporal relationship between the incidence of upper respiratory tract infection symptoms and immune system changes following excessive exercise load (EEL) have not been shown. T-helper cells are functionally polarised according to the cytokines which they produce. While exercise-induced upregulation of T-helper- 2 (TH2) cells and type 2 cytokines is indicative of enhanced activation of allergic responses, downregulation of T-helper-1 (TH1) cells and type 1 cytokines confirms suppression of cellular immune functions. The current knowledge regarding the exercise-induced kinetics of interleukin (IL)-4, a cytokine that is crucial in the activation of the TH2 cells, does, however, not appear to provide sufficient support for an upregulation of a type 2 response. Lowered or unchanged circulating concentrations of type1 cytokines (IL12, IL-2 and interferon &gamma;) and short-term suppression of lymphocyte, natural killer cell and neutrophil function following EEL, reflect a transient, post-exercise suppression of cellular immunity. Despite a partial dampening thereof by the anti-inflammatory actions of IL-10, IL-1ra and IL-6, the evidence supporting a pro-inflammatory response to prolonged exercise and overtraining is unequivocal. At present, the data appear to support the theory that symptoms of ‘infection' experienced by athletes are the manifestation of a significant pro-inflammatory response, combined with a modest, transient suppression of cellular immune functions which may be clinically insignificant. South African Journal of Sports Medicine Vol.16(1) 2004: 3-

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

Age-related delay in information accrual for faces: Evidence from a parametric, single-trial EEG approach

Background: In this study, we quantified age-related changes in the time-course of face processing by means of an innovative single-trial ERP approach. Unlike analyses used in previous studies, our approach does not rely on peak measurements and can provide a more sensitive measure of processing delays. Young and old adults (mean ages 22 and 70 years) performed a non-speeded discrimination task between two faces. The phase spectrum of these faces was manipulated parametrically to create pictures that ranged between pure noise (0% phase information) and the undistorted signal (100% phase information), with five intermediate steps. Results: Behavioural 75% correct thresholds were on average lower, and maximum accuracy was higher, in younger than older observers. ERPs from each subject were entered into a single-trial general linear regression model to identify variations in neural activity statistically associated with changes in image structure. The earliest age-related ERP differences occurred in the time window of the N170. Older observers had a significantly stronger N170 in response to noise, but this age difference decreased with increasing phase information. Overall, manipulating image phase information had a greater effect on ERPs from younger observers, which was quantified using a hierarchical modelling approach. Importantly, visual activity was modulated by the same stimulus parameters in younger and older subjects. The fit of the model, indexed by R2, was computed at multiple post-stimulus time points. The time-course of the R2 function showed a significantly slower processing in older observers starting around 120 ms after stimulus onset. This age-related delay increased over time to reach a maximum around 190 ms, at which latency younger observers had around 50 ms time lead over older observers. Conclusion: Using a component-free ERP analysis that provides a precise timing of the visual system sensitivity to image structure, the current study demonstrates that older observers accumulate face information more slowly than younger subjects. Additionally, the N170 appears to be less face-sensitive in older observers