The construction, demolition and excavation waste arising in England was estimated at 91 million tonnes in 2003. The current thinking on construction waste minimisation is heavily focussed on several ...issues relating to physical construction waste and recycling guides. Indeed, much had been published on ways to improve on-site waste management and recycling activities but very few attempts made to address the effect of design practices on waste generation. However, there is a consensus in the literature that the architect has a decisive role to play in helping to reduce waste by focussing on designing out waste. This paper examines previous studies on architects’ approach towards construction waste minimisation; and by means of a postal questionnaire, investigates: the origins of waste; waste minimisation design practices in the UK; and responsibilities and barriers within the UK architectural profession.
The findings reveal that waste management is not a priority in the design process. Additionally, the architects seemed to take the view that waste is mainly produced during site operations and rarely generated during the design stages; however, about one-third of construction waste could essentially arise from design decisions. Results also indicate that a number of constraints, namely: lack of interest from clients; attitudes towards waste minimisation; and training all act as disincentives to a proactive and sustainable implementation of waste reduction strategies during the design process.
Skeletal muscles adapt to changes in their workload by regulating fibre size by unknown mechanisms. The roles of two signalling pathways implicated in muscle hypertrophy on the basis of findings in ...vitro, Akt/mTOR (mammalian target of rapamycin) and calcineurin/NFAT (nuclear factor of activated T cells), were investigated in several models of skeletal muscle hypertrophy and atrophy in vivo. The Akt/mTOR pathway was upregulated during hypertrophy and downregulated during muscle atrophy. Furthermore, rapamycin, a selective blocker of mTOR, blocked hypertrophy in all models tested, without causing atrophy in control muscles. In contrast, the calcineurin pathway was not activated during hypertrophy in vivo, and inhibitors of calcineurin, cyclosporin A and FK506 did not blunt hypertrophy. Finally, genetic activation of the Akt/mTOR pathway was sufficient to cause hypertrophy and prevent atrophy in vivo, whereas genetic blockade of this pathway blocked hypertrophy in vivo. We conclude that the activation of the Akt/mTOR pathway and its downstream targets, p70S6K and PHAS-1/4E-BP1, is requisitely involved in regulating skeletal muscle fibre size, and that activation of the Akt/mTOR pathway can oppose muscle atrophy induced by disuse.
HDAC4, a class IIa histone deacetylase, is upregulated in skeletal muscle in response to denervation-induced atrophy. When HDAC4 is deleted postnatally, mice are partially protected from denervation. ...Despite the name “histone” deacetylase, HDAC4 demonstrably deacetylates cytosolic and non-histone nuclear proteins. We developed potent and selective class IIa HDAC inhibitors. Using these tools and genetic knockdown, we identified three previously unidentified substrates of HDAC4: myosin heavy chain, peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1α), and heat shock cognate 71 kDa protein (Hsc70). HDAC4 inhibition almost completely prevented denervation-induced loss of myosin heavy chain isoforms and blocked the action of their E3 ligase, MuRF1. PGC-1α directly interacts with class IIa HDACs; selective inhibitors increased PGC-1α protein in muscles. Hsc70 deacetylation by HDAC4 affects its chaperone activity. Through these endogenous HDAC4 substrates, we identified several muscle metabolic pathways that are regulated by class IIa HDACs, opening up new therapeutic options to treat skeletal muscle disorders and potentially other disease where these specific pathways are affected.
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•HDAC4 is an active enzyme•HDAC4 deacetylates myosin heavy chain, PGC-1α, and Hsc70•HDAC4 inhibition increases myosin heavy chain and PGC-1α protein levels•Maintaining acetylation of myosin heavy chain and Hsc70 prevents atrophy
Luo et al. use class IIa HDAC inhibitors, along with skeletal-muscle-specific and whole-body inducible HDAC4 knockout mice, to demonstrate HDAC4 deacetylates three previously undescribed substrates: myosin heavy chain, PGC-1α, and Hsc70. Through these substrates, HDAC4 inhibition leads to rescue of muscle atrophy and increased succinate dehydrogenase activity.
Abstract
Background
There is growing evidence that neuroinflammation may contribute to schizophrenia neuropathology. Elevated pro-inflammatory cytokines are evident in the midbrain from schizophrenia ...subjects, findings that are driven by a subgroup of patients, characterised as a “high inflammation” biotype. Cytokines trigger the release of antibodies, of which immunoglobulin G (IgG) is the most common. The level and function of IgG is regulated by its transporter (FcGRT) and by pro-inflammatory IgG receptors (including FcGR3A) in balance with the anti-inflammatory IgG receptor FcGR2B. Testing whether abnormalities in IgG activity contribute to the neuroinflammatory abnormalities schizophrenia patients, particularly those with elevated cytokines, may help identify novel treatment targets.
Methods
Post-mortem midbrain tissue from healthy controls and schizophrenia cases (
n
= 58 total) was used to determine the localisation and abundance of IgG and IgG transporters and receptors in the midbrain of healthy controls and schizophrenia patients. Protein levels of IgG and FcGRT were quantified using western blot, and gene transcript levels of FcGRT, FcGR3A and FcGR2B were assessed using qPCR. The distribution of IgG in the midbrain was assessed using immunohistochemistry and immunofluorescence. Results were compared between diagnostic (schizophrenia vs control) and inflammatory (high vs low inflammation) groups.
Results
We found that IgG and FcGRT protein abundance (relative to β-actin) was unchanged in people with schizophrenia compared with controls irrespective of inflammatory subtype. In contrast, FcGRT and FcGR3A mRNA levels were elevated in the midbrain from “high inflammation” schizophrenia cases (FcGRT;
p
= 0.02, FcGR3A;
p
< 0.0001) in comparison to low-inflammation patients and healthy controls, while FcGR2B mRNA levels were unchanged. IgG immunoreactivity was evident in the midbrain, and approximately 24% of all individuals (control subjects and schizophrenia cases) showed diffusion of IgG from blood vessels into the brain. However, the intensity and distribution of IgG was comparable across schizophrenia cases and control subjects.
Conclusion
These findings suggest that an increase in the pro-inflammatory Fcγ receptor FcGR3A, rather than an overall increase in IgG levels, contribute to midbrain neuroinflammation in schizophrenia patients. However, more precise information about IgG-Fcγ receptor interactions is needed to determine their potential role in schizophrenia neuropathology.
Toll-like receptors (TLRs) are a family of pattern recognition receptors that are an important link between innate and adaptive immunity. Many vaccines incorporate ligands for TLRs as an adjuvant and ...are developed in rodent models, with the resulting data transferred to other species. Vaccine features can be improved markedly by emphasizing the biological relevance when evaluating other animal models for host-pathogen interaction and by taking greater advantage of the unique experimental opportunities that are offered by large animal, non-rodent models. Here, we aim to summarize our current knowledge of species-specific TLR responses and briefly discuss that vaccine efficacy in relevant host species might be improved by considering the species-specific TLR responses.
Microgravity exposure is associated with loss of muscle mass and strength. The E3 ubiquitin ligase MuRF1 plays an integral role in degrading the contractile apparatus of skeletal muscle; MuRF1 null ...(KO) mice have shown protection in ground-based models of muscle atrophy. In contrast, MuRF1 KO mice subjected to 21 days of microgravity on the International Space Station (ISS) were not protected from muscle atrophy. In a time course experiment microgravity-induced muscle loss on the ISS showed MuRF1 gene expression was not upregulated. A comparison of the soleus transcriptome profiles between spaceflight and a publicly available data set for hindlimb suspension, a claimed surrogate model of microgravity, showed only marginal commonalities between the models. These findings demonstrate spaceflight induced atrophy is unique, and that understanding of effects of space requires study situated beyond the Earth's mesosphere.
PFS occurs in approximately 25% of pediatric patients receiving surgery for midline posterior fossa tumors. Increasing evidence suggests that PFS represents a complex supratentorial cortical ...dysfunction related to surgery-induced disruption of critical cerebellocerebral connections. The purpose of this study was to determine whether a consistent surgical damage pattern may be identified in patients with PFS by early postoperative anatomic imaging analysis of the pECP and to test whether DSC can detect corresponding changes in cerebral cortical perfusion to indicate a secondary, remote functional disturbance, which could suggest a diaschisis-like pathomechanism.
Eleven patients with postoperative PFS were evaluated retrospectively and were paired with age- and sex-matched control subjects in whom PFS did not develop. MR imaging work-up included DSC within 3 to 4 weeks after surgery as well as early postoperative anatomic imaging to evaluate components of the pECP.
DSC showed significant decreases in CBF within frontal regions (P < .05) and a trend to global cerebral cortical hypoperfusion in patients with PFS. Logistic regression analysis suggested a strong (potentially predictive) relationship between bilateral damage to pECP and the development of PFS (P = .04).
Our data suggest that the primary cause of PFS is the bilateral surgical damage to the pECP. This leads to a trans-synaptic cerebral cortical dysfunction (a form of bilateral crossed cerebellocerebral diaschisis), which manifests with DSC-detectable global, but dominantly frontal, cortical hypoperfusion in patients with patients with PFS compared with age- and sex-matched control subjects.
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