By designing a structured gas density profile between the dual-stage gas jets to manipulate electron seeding and energy chirp reversal for compressing the energy spread, we have experimentally ...produced high-brightness high-energy electron beams from a cascaded laser wakefield accelerator with peak energies in the range of 200-600 MeV, 0.4%-1.2% rms energy spread, 10-80 pC charge, and ∼0.2 mrad rms divergence. The maximum six-dimensional brightness B_{6D,n} is estimated as ∼6.5×10^{15} A/m^{2}/0.1%, which is very close to the typical brightness of e beams from state-of-the-art linac drivers. These high-brightness high-energy e beams may lead to the realization of compact monoenergetic gamma-ray and intense coherent x-ray radiation sources.
Abstract There are indications for changes in glutamate metabolism in relation to depression or suicide. The glutamate-glutamine cycle and neuronal/glial glutamate transporters mediate the uptake of ...the glutamate and glutamine. The expression of various components of the glutamate-glutamine cycle and the neuronal/glial glutamate transporters was determined by qPCR in postmortem prefrontal cortex. The anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC) were selected from young MDD patients who had committed suicide (MDD-S; n = 17), from MDD patients who died of non-suicide related causes (MDD-NS; n = 7) and from matched control subjects (n = 12). We also compared elderly depressed patients who had not committed suicide (n = 14) with matched control subjects (n = 22). We found that neuronal located components (EAAT3, EAAT4, ASCT1, SNAT1, SNAT2) of the glutamate-glutamine cycle were increased in the ACC while the astroglia located components (EAAT1, EAAT2, GLUL) were decreased in the DLPFC of MDD-S patients. In contrast, most of the components in the cycle were increased in the DLPFC of MDD-NS patients. In conclusion, the glutamate-glutamine cycle - and thus glutamine transmission - is differentially affected in depressed suicide patients and depressed non-suicide patients in an area specific way.
A simple, efficient scheme was developed to obtain near-gigaelectronvolt electron beams with energy spreads of few per-mille level in a single-stage laser wakefield accelerator. Longitudinal plasma ...density was tailored to control relativistic laser-beam evolution, resulting in injection, dechirping, and a quasi-phase-stable acceleration. With this scheme, electron beams with peak energies of 780–840 MeV, rms energy spreads of 2.4‰–4.1‰, charges of 8.5–23.6 pC, and rms divergences of 0.1–0.4 mrad were experimentally obtained. Quasi-three-dimensional particle-in-cell simulations agreed well with the experimental results. The dechirping strength was estimated to reach up to 11 TeV/mm/m, which is higher than previously obtained results. Such high-quality electron beams will boost the development of compact intense coherent radiation sources and x-ray free-electron lasers.
People that committed suicide were reported to have enhanced levels of gene transcripts for synaptic proteins in their prefrontal cortex (PFC). Given the close association of suicide with major ...depressive disorder (MDD), we here assessed whether these changes are related to suicide or rather to depression per se.
We used quantitative PCR to determine mRNA levels of 32 genes encoding for proteins directly involved in glutamatergic or GABAergic synaptic transmission in postmortem samples of the anterior cingulate cortex (ACC) and the dorsolateral PFC (DLPFC). Seventy-two brain samples from 3 groups of subjects were derived from the Stanley Medical Research Institute (SMRI): i) patients with MDD who committed suicide (MDD-S), ii) MDD patients who died of non-suicidal causes (MDD-NS) and iii) age-matched, non-psychiatric control subjects.
In the ACC, a significantly enhanced expression of genes related to glutamatergic or GABAergic synaptic transmission was found only in MDD-S patients, whereas in MDD-NS patients, decreased levels for these transcripts were found. Moreover, in the DLPFC, expression of these genes was decreased in MDD-S, relative to MDD-NS patients, whereas both groups showed increased expression compared to control subjects.
In conclusion, our findings indicate that MDD is associated with increases in GABA and glutamate related genes in the DLPFC (irrespective of suicide), while in the ACC, the increase in GABA and glutamate related genes may relate to suicide, rather than to MDD per se.
Background
Hyperthermia upregulates DNAJA4, a member of heat shock proteins (HSPs) 40 family, in human keratinocytes and HPV‐infected tissue. DNAJA4 deficiency enhances growth arrest induced by ...hyperthermia. Clusterin (CLU) and phosphorylated ERK (p‐ERK) play a role in regulating cell proliferation and apoptosis, under environmental stress.
Objectives
To examine the downstream molecules and signalling pathways of DNAJA4 and assess their roles in cell cycle and apoptosis of keratinocytes in response to hyperthermia.
Methods
Wild‐type and DNAJA4‐knockout (KO) HaCaT cells were exposed to either 44 °C (hyperthermia) or 37 °C (control) for 30 min. The expression levels of CLU and p‐ERK were determined by RT‐PCR and Western blotting. RNAi and PD98059 were used to inhibit the expression of CLU and p‐ERK, respectively. Cell viability, cell cycle and apoptosis were analysed by MTS assay and flow cytometry. Fresh biopsy samples of human normal foreskin or condyloma acuminatum (CA) were utilized to examine the expression of CLU and p‐ERK after ex vivo culture at 44 °C.
Results
The expression of CLU and p‐ERK was significantly increased by hyperthermia treatment at 44 °C in HaCaT cells, foreskin and HPV‐infected tissues. In HaCaT cells subjected to hyperthermia, DNAJA4 deficiency further augmented the expression of CLU and p‐ERK. CLU deficiency enhanced the p‐ERK expression. Hyperthermia‐induced CLU and p‐ERK exerted protective roles mainly through inhibiting apoptosis and maintaining cell cycle, respectively.
Conclusions
In keratinocytes, CLU and p‐ERK are induced by hyperthermia, an effect which can be further enhanced by DNAJA4 deficiency. CLU deficiency also increases p‐ERK expression. Both CLU and p‐ERK are critical protective factors of human keratinocytes from hyperthermia‐induced injury.
CREB is an ubiquitous transcription factor regulating diverse cellular responses. Its phosphorylation at S133 is an essential event for its activation in both nervous and visual systems. The ...activated CREB is implicated in the regulation of development, protection, learning, memory and plasticity in the nerve system. Moreover, sumoylation, an important post-translational modification of protein, plays a key role in sustaining CREB activation in the rat hippocampus in order to enhance the long-term memory and other aspects. In the visual system, although the CREB activation by phosphorylation at S133 is similar to that as observed in the nervous system, the role of CREB sumoylation remains to be explored. This review will discuss the aspects of CREB functions and their regulation by phosphorylation and sumoylation in both systems.
The aim of this study was to determine whether Lactobacillus rhamnosus GG (LGG) components (surface layer protein, SLP; genomic DNA, gDNA; unmethylated cytosine‐phosphate‐guanine‐containing ...oligodeoxynucleotide, CpG‐ODN), alone or in combination, could affect immunomodulation, and evaluate the signalling mechanism in mouse macrophage RAW264.7 cells challenged with lipopolysaccharide (LPS). LGG components were used to treat cells before LPS stimulation. Cytokine and Toll‐like receptor (TLR) expression were assessed using real‐time quantitative PCR (RT‐qPCR). Mitogen‐activated protein kinase (MAPK), extracellular regulated protein kinase (ERK) and nuclear factor‐kappa B (NF‐κB) signalling pathways were evaluated using immunoblots and immunofluorescence. SLP or SLP + gDNA pre‐treatment significantly reduced the LPS‐induced mRNA expression of tumour necrosis factor alpha (TNF‐α). Pre‐treatment with LGG single components (SLP, gDNA or CpG) or their combinations (SLP + gDNA or SLP + CpG) significantly decreased the LPS‐induced interleukin‐6 (IL‐6) mRNA level (P < 0·05). Pre‐treatment with SLP or gDNA, alone or in combination, significantly suppressed LPS‐induced TLR2 and TLR4 mRNA levels (P < 0·05). SLP pre‐treatment also significantly decreased the LPS‐induced expression of TLR9 (P < 0·05). Pre‐treatment with LGG single components or combinations significantly suppressed the LPS‐induced phosphorylation levels of ERK (P > 0·05). In conclusion, pre‐incubation with LGG components, singly or in combination, generally inhibited the activation of TLR, MAPK and NF‐κB signalling pathways in LPS‐stimulated cells, leading to attenuated inflammatory cytokine TNF‐α and IL‐6 production. These results indicate that nonviable probiotic LGG components exert an anti‐inflammation effect on epithelial cells.
Significance and Impact of the Study
Lactobacillus rhamnosus GG (LGG) is widely used as probiotics. However, its main components are not well known for affecting immunomodulation. This study investigated the effects of pre‐treatments with different components such as surface layer protein, genomic DNA and unmethylated cytosine‐phosphate‐guanine‐containing oligodeoxynucleotides, alone or in combination on immunomodulation, and evaluated the signalling mechanism in mouse macrophage RAW264.7 cells challenged with lipopolysaccharide. Pre‐incubation with components alone or in combination generally inhibited the activation of Toll‐like receptor, mitogen‐activated protein kinases, extracellular regulated protein kinases and nuclear factor‐kappa B signalling pathways in lipopolysaccharide‐stimulated cells, which generally leads to attenuated inflammatory cytokine interleukin‐6 and tumour necrosis factor alpha production. These results indicate that nonviable probiotic LGG components exert an anti‐inflammation effect on epithelial cells.
Significance and Impact of the Study: Lactobacillus rhamnosus GG (LGG) is widely used as probiotics. However, its main components are not well known for affecting immunomodulation. This study investigated the effects of pre‐treatments with different components such as surface layer protein, genomic DNA and unmethylated cytosine‐phosphate‐guanine‐containing oligodeoxynucleotides, alone or in combination on immunomodulation, and evaluated the signalling mechanism in mouse macrophage RAW264.7 cells challenged with lipopolysaccharide. Pre‐incubation with components alone or in combination generally inhibited the activation of Toll‐like receptor, mitogen‐activated protein kinases, extracellular regulated protein kinases and nuclear factor‐kappa B signalling pathways in lipopolysaccharide‐stimulated cells, which generally leads to attenuated inflammatory cytokine interleukin‐6 and tumour necrosis factor alpha production. These results indicate that nonviable probiotic LGG components exert an anti‐inflammation effect on epithelial cells.
SUMOylation in Neurological Diseases Liu, F-Y; Liu, Y-F; Yang, Y ...
Current molecular medicine,
12/2016, Letnik:
16, Številka:
10
Journal Article
Recenzirano
Since the discovery of SUMOs (small ubiquitin-like modifiers) over 20 years ago, sumoylation has recently emerged as an important posttranslational modification involved in almost all aspects of ...cellular physiology. In neurons, sumoylation dynamically modulates protein function and consequently plays an important role in neuronal maturation, synapse formation and plasticity. Thus, the dysfunction of sumoylation pathway is associated with many different neurological disorders. Hundreds of different proteins implicated in the pathogenesis of neurological disorders are SUMO-modified, indicating the importance of sumoylation involved in the neurological diseases. In this review, we summarize the growing findings on protein sumoylation in neuronal function and dysfunction. It is essential to have a thorough understanding on the mechanism how sumoylation contributes to neurological diseases in developing efficient therapy for these diseases.
Sumoylation, a post-translational modification discovered over a decade ago, turns out to be a very important regulatory mechanism mediating multiple cellular processes. Recent studies from our ...laboratory and others also revealed that it plays a crucial role in regulating both differentiation and pathogenesis of the ocular lens. This review will summarize these progresses.
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