Prohibitin (PHB) is indispensable for Ras-induced Raf-1 activation, cell migration and growth; however, the exact role of PHB in the molecular pathogenesis of cancer metastasis remains largely ...unexamined. Here, we found a positive correlation between plasma membrane-associated PHB and the clinical stages of cancer. The level of PHB phosphorylated at threonine 258 (T258) and tyrosine 259 (Y259) in human cancer-cell membranes correlated with the invasiveness of cancer cells. Overexpression of phosphorylated PHB (phospho-PHB) in the lipid-raft domain of the cell membrane enhanced cell migration/invasion through PI3K/Akt and Raf-1/ERK activation. It also enhanced epithelial-mesenchymal transition, matrix metalloproteinase-2 activity and invasiveness of cancer cells in vitro. Immunoprecipitation analysis demonstrated that phospho-PHB associated with Raf-1, Akt and Ras in the membrane and was essential for the activation of Raf-1 signaling by Ras. Mice implanted with cancer cells stably overexpressing PHB in the plasma membrane showed enlarged cervical tumors, enhanced metastasis and shorter survival time compared with mice implanted with cancer cells without PHB overexpression. Dephosphorylation of PHB at T258 by site-directed mutagenesis diminished the in vitro and in vivo effects of PHB. These results suggest that increase in phospho-PHB T258 in the raft domain of the plasma membrane has a role in the Ras-driven activation of PI3K/Akt and Raf-1/ERK-signaling cascades and results in the promotion of cancer metastasis.
Whether primary sensory cortices are essentially multisensory or whether they respond to only one sense is an emerging debate in neuroscience. Here we use a multivariate pattern analysis of ...functional magnetic resonance imaging data in humans to demonstrate that simple and isolated stimuli of one sense elicit distinguishable spatial patterns of neuronal responses, not only in their corresponding primary sensory cortex, but in other primary sensory cortices. These results indicate that primary sensory cortices, traditionally regarded as unisensory, contain unique signatures of other senses and, thereby, prompt a reconsideration of how sensory information is coded in the human brain.
Brain-derived neurotrophic factor (BDNF) has been strongly implicated in the synaptic plasticity, neuronal survival and pathophysiology of depression. Lithium and valproic acid (VPA) are two primary ...mood-stabilizing drugs used to treat bipolar disorder. Treatment of cultured rat cortical neurons with therapeutic concentrations of LiCl or VPA selectively increased the levels of exon IV (formerly rat exon III)-containing BDNF mRNA, and the activity of BDNF promoter IV. Surprisingly, lithium- or VPA-responsive element(s) in promoter IV resides in a region upstream from the calcium-responsive elements (CaREs) responsible for depolarization-induced BDNF induction. Moreover, activation of BDNF promoter IV by lithium or VPA occurred in cortical neurons depolarized with KCl, and deletion of these three CaREs did not abolish lithium- or VPA-induced activation. Lithium and VPA are direct inhibitors of glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC), respectively. We showed that lithium-induced activation of promoter IV was mimicked by pharmacological inhibition of GSK-3 or short interfering RNA (siRNA)-mediated gene silencing of GSK-3alpha or GSK-3beta isoforms. Furthermore, treatment with other HDAC inhibitors, sodium butyrate and trichostatin A, or transfection with an HDAC1-specific siRNA also activated BDNF promoter IV. Our study demonstrates for the first time that GSK-3 and HDAC are respective initial targets for lithium and VPA to activate BDNF promoter IV, and that this BDNF induction involves a novel responsive region in promoter IV of the BDNF gene. Our results have strong implications for the therapeutic actions of these two mood stabilizers.
SFTS virus (SFTSV) is a novel bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS), an emerging infectious disease that occurred in China in recent years, with an average case ...fatality rate of 10–12%. Intervention in the early clinical stage is the most effective measure to reduce the mortality rate of disease. To elucidate the natural course of and immune mechanisms associated with the pathogenesis of SFTSV, 59 laboratory-confirmed SFTS patients in the acute phase, who were hospitalized between October 2010 and September 2011, were enrolled in this study, and the patients sera were dynamically collected and tested for SFTSV viral RNA load, 34 cytokines or chemokines and other related laboratory parameters. All clinical diagnostic factors in the acute phase of SFTS were evaluated and assessed. The study showed that the severity of the disease in 11 (18.6%) patients was associated with abdominal pain (p 0.007; OR = 21.95; 95% CI, 2.32–208.11) and gingival bleeding (p 0.001; OR = 122.11; 95% CI, 6.41–2328). The IP-10, TNF-α, IL-6, IL-10, granzyme B and HSP70 levels were higher over the 7–8 days in severe cases, accompanied by altered AST, CK and LDH levels. HSP70 (p 0.012; OR = 8.29; 95% CI, 1.58–43.40) was independently correlated with the severity of the early acute phase of SFTSV infection. The severity of SFTS can be predicted based on the presence of symptoms such as abdominal pain and gingival bleeding and on the level of HSP70 in the acute phase of the disease.
Protein folding can begin co-translationally. Due to the difference in timescale between folding and synthesis, co-translational folding is thought to occur at equilibrium for fast-folding domains. ...In this scenario, the folding kinetics of stalled ribosome-bound nascent chains should match the folding of nascent chains in real time. To test if this assumption is true, we compare the folding of a ribosome-bound, multi-domain calcium-binding protein stalled at different points in translation with the nascent chain as is it being synthesized in real-time, via optical tweezers. On stalled ribosomes, a misfolded state forms rapidly (1.5 s). However, during translation, this state is only attained after a long delay (63 s), indicating that, unexpectedly, the growing polypeptide is not equilibrated with its ensemble of accessible conformations. Slow equilibration on the ribosome can delay premature folding until adequate sequence is available and/or allow time for chaperone binding, thus promoting productive folding.
Highlights • Gastrodin improves learning and memory abilities of Tg2576 mice. • Gastrodin attenuates intracellular oxidative stress in hippocampi of Tg2576 mice. • Gastrodin suppresses BACE1 ...expression and PKR/eIF2α pathway in hippocampi of Tg2576 mice. • Gastrodin suppresses BACE1 via inhibiting PKR/eIF2α in SH-SY5Y cells under oxidative stress.
Fusarium species are important cereal pathogens that cause severe production losses to major cereal crops such as maize, rice, and wheat. However, the causal agents of Fusarium diseases on cereals ...have not been well documented because of the difficulty in species identification and the debates surrounding generic and species concepts. In this study, we used a citizen science initiative to investigate diseased cereal crops (maize, rice, wheat) from 250 locations, covering the major cereal-growing regions in China. A total of 2 020 Fusarium strains were isolated from 315 diseased samples. Employing multi-locus phylogeny and morphological features, the above strains were identified to 43 species, including eight novel species that are described in this paper. A world checklist of cereal-associated Fusarium species is provided, with 39 and 52 new records updated for the world and China, respectively. Notably, 56 % of samples collected in this study were observed to have co-infections of more than one Fusarium species, and the detailed associations are discussed. Following Koch’s postulates, 18 species were first confirmed as pathogens of maize stalk rot in this study. Furthermore, a high-confidence species tree was constructed in this study based on 1 001 homologous loci of 228 assembled genomes (40 genomes were sequenced and provided in this study), which supported the “narrow” generic concept of Fusarium (= Gibberella ). This study represents one of the most comprehensive surveys of cereal Fusarium diseases to date. It significantly improves our understanding of the global diversity and distribution of cereal-associated Fusarium species, as well as largely clarifies the phylogenetic relationships within the genus.
Summary
The rationale of this study was to examine the effectiveness of 6-month high-impact step aerobics (SA) or moderate-intensity resistance training exercise (RT) on bone mineral density (BMD) ...and bone bending strength in sedentary women. Results show that SA enhanced BMD in the heel, lower leg, and lumbar spine 2.
Introduction
To determine the effectiveness of 6 months of high-impact step aerobics (SA) or moderate-intensity resistance training (RT) on areal bone mineral density (aBMD) and tibial bending strength in sedentary premenopausal women.
Methods
Sixty-nine women (20–35 years old) who were randomly assigned to RT (
n
= 22), SA (
n
= 26), or non-treatment control (CON,
n
= 21) groups completed the study. SA had a minimum of 50 high-impact landings each training session. RT had a periodized lower body resistance training program incorporating eight exercises (65–85% of 1 repetition maximum: 1-RM). Both RT and SA met 3 times weekly. aBMD was assessed using dual X-ray absorptiometry (DXA). Tibial bending strength was assessed using mechanical response tissue analysis (MRTA). Measurements at 6 months were compared to baseline using ANCOVA, adjusted for baseline measures and covariates with
α
= 0.05.
Results
Calcaneus aBMD (0.0176 vs -0.0019 or -0.0009 g/cm
2
relative to RT,
p
< 0.004, and CON,
p
< 0.006, respectively), lower leg aBMD (0.0105 vs -0.0036 g/cm
2
, relative to RT,
p
= 0.02), and lumbar spine 2 (L2) aBMD (0.0082 vs -0.0157 g/cm
2
relative to CON,
p
< 0.02) were significantly greater in the SA group after 6 months. Tibial bending strength and bone resorption biomarkers were unchanged in all three groups after 6 months.
Conclusion
Sedentary premenopausal women engaging in 6 months of high-impact aerobic exercise improved aBMD in the calcaneus, lower leg, and L2.
Forests play a critical role in stabilizing Earth's climate. Establishing protected areas (PAs) represents one approach to forest conservation, but PAs were rarely created to mitigate climate change. ...The global impact of PAs on the carbon cycle has not previously been quantified due to a lack of accurate global-scale carbon stock maps. Here we used ~412 million lidar samples from NASA's GEDI mission to estimate a total PA aboveground carbon (C) stock of 61.43 Gt (+/- 0.31), 26% of all mapped terrestrial woody C. Of this total, 9.65 + /- 0.88 Gt of additional carbon was attributed to PA status. These higher C stocks are primarily from avoided emissions from deforestation and degradation in PAs compared to unprotected forests. This total is roughly equivalent to one year of annual global fossil fuel emissions. These results underscore the importance of conservation of high biomass forests for avoiding carbon emissions and preserving future sequestration.
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