Neuroplasticity hypothesis of the mechanism of electroconvulsive therapy: a proton magnetic resonance and functional connectivity investigation

INTRODUCTION: Major depressive disorder (MDD) is characterized by ongoing feelings of guilt, sadness, and memory and cognition impairment. It is a multidimensional illness that affects many functionally integrated pathways of the brain. Understanding the underlying brain dysfunction that gives rise to this complex illness has been challenging, and by extension the search for appropriate treatments. MDD patients who are considered treatment resistant make up the primary population that receives electroconvulsive therapy (ECT). Remarkably, ECT shows a 75% remission rate in this patient population and is considered the “gold standard” treatment for major depression. Although the exact mechanism of its function is unknown, it is well accepted that the induced grand-mal seizure confers its therapeutic effect. The seizure likely has broad effect that somehow corrects the underlying dysfunction in brain circuitry. Here, we specifically examined studies of functional connectivity and metabolite changes. METHODS: Through literature search, we examined six studies in functional connectivity and four studies in magnetic resonance spectroscopy (MRS). RESULTS: Functional Connectivity: Studies have found that after bilateral ECT treatments, patients with major depression showed reduction of functional connectivity (FC) from the left dorsolateral prefrontal cortex (DLPFC) to other cortical and limbic structures. Correlated activity between the superior frontal gyri, middle frontal gyri and angular gyri were significantly increased after ECT. Hyperdeactivation of the orbitofrontal cortex to negative emotional stimuli in patients was decreased, and it was associated with improvement in depressive symptoms. Regional activity in the subgenual anterior cingulate cortex (sgACC) and functional connectivity between the sgACC and left hippocampus in treatment naïve patients after ECT were increased and correlated to reduction of depressive symptoms. Reduced connectivity between the amygdale and sgACC and increased connectivity between the amygdale and DLPFC was found by sequential assessments over a course of ECT treatments. Lastly, ECT increased the functional connectivity between DLPFC and the default mode network. MRS: Studies found decreased levels of glutamate or glx (glutamate/glutamine/ GABA) in patients in the anterior cingulate cortex and dorsolateral prefrontal cortex (DLPFC) compared to healthy controls. Additionally, it was found that glx levels increased after ECT treatments and that this increase was only in those who responded to treatment. Lastly, GABA level increased after ECT treatment in the occipital cortex. Discussion: Results from functional connectivity and brain metabolite studies in patients with major depression point to induced neuroplasticity as part of ECT’s therapeutic mechanism. Remodeling connectivity and mediating metabolite changes both will require modifications at the synaptic level. The wide spread changes seen in several different brain regions that have been implicated in depression further suggests that ECT’s effects are both highly specific and broad. CONCLUSION: Electroconvulsive therapy has consistently demonstrated impressive efficacy among the most severely depressed patients and is known to produce widely distributed effects in the brain. However, this also makes assessing its therapeutic mechanism challenging. Magnetic resonance imaging studies assessing functional connectivity and brain metabolite levels have demonstrated that ECT likely produces neuroplastic changes to remodel aberrant connectivity and dysfunctional excitatory and inhibitory neurotransmission in cortical and limbic areas. Although these findings should be interpreted with caution, this field of research has provided an unprecedented opportunity to examine the living brain in great detail. Further studies with larger sample sizes and improved technical specifications will likely yield greater results

On Weak Exponential Expansiveness of Evolution Families in Banach Spaces

The aim of this paper is to give several characterizations for the property of weak exponential expansiveness for evolution families in Banach spaces. Variants for weak exponential expansiveness of some well-known results in stability theory (Datko (1973), Rolewicz (1986), Ichikawa (1984), and Megan et al. (2003)) are obtained

MAPK1 promotes the metastasis and invasion of gastric cancer as a bidirectional transcription factor

Background: The Mitogen-activated protein kinase 1 (MAPK1) has both independent functions of phosphorylating histones as a kinase and directly binding the promoter regions of genes to regulate gene expression as a transcription factor. Previous studies have identified elevated expression of MAPK1 in human gastric cancer, which is associated with its role as a kinase, facilitating the migration and invasion of gastric cancer cells. However, how MAPK1 binds to its target genes as a transcription factor and whether it modulates related gene expressions in gastric cancer remains unclear. Results: Here, we integrated biochemical assays (protein interactions and chromatin immunoprecipitation (ChIP)), cellular analysis assays (cell proliferation and migration), RNA sequencing, ChIP sequencing, and clinical analysis to investigate the potential genomic recognition patterns of MAPK1 in a human gastric adenocarcinoma cell-line (AGS) and to uncover its regulatory effect on gastric cancer progression. We confirmed that MAPK1 promotes AGS cells invasion and migration by regulating the target genes in different directions, up-regulating seven target genes (KRT13, KRT6A, KRT81, MYH15, STARD4, SYTL4, and TMEM267) and down-regulating one gene (FGG). Among them, five genes (FGG, MYH15, STARD4, SYTL4, and TMEM267) were first associated with cancer procession, while the other three (KRT81, KRT6A, and KRT13) have previously been confirmed to be related to cancer metastasis and migration. Conclusion: Our data showed that MAPK1 can bind to the promoter regions of these target genes to control their transcription as a bidirectional transcription factor, promoting AGS cell motility and invasion. Our research has expanded the understanding of the regulatory roles of MAPK1, enriched our knowledge of transcription factors, and provided novel candidates for cancer therapeutics

Local melting to design strong and plastically deformable bulk metallic glass composites

Recently, CuZr-based bulk metallic glass (BMG) composites reinforced by the TRIP (transformation-induced plasticity) effect have been explored in attempt to accomplish an optimal of trade-off between strength and ductility. However, the design of such BMG composites with advanced mechanical properties still remains a big challenge for materials engineering. In this work, we proposed a technique of instantaneously and locally arc-melting BMG plate to artificially induce the precipitation of B2 crystals in the glassy matrix and then to tune mechanical properties. Through adjusting local melting process parameters (i.e. input powers, local melting positions, and distances between the electrode and amorphous plate), the size, volume fraction, and distribution of B2 crystals were well tailored and the corresponding formation mechanism was clearly clarified. The resultant BMG composites exhibit large compressive plasticity and high strength together with obvious work-hardening ability. This compelling approach could be of great significance for the steady development of metastable CuZr-based alloys with excellent mechanical properties

Cholesteryl Ester Accumulation Induced by PTEN Loss and PI3K/AKT Activation Underlies Human Prostate Cancer Aggressiveness

Altered lipid metabolism is increasingly recognized as a signature of cancer cells. Enabled by label-free Raman spectromicroscopy, we performed quantitative analysis of lipogenesis at single cell level in human patient cancerous tissues. Our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases. Biochemical study showed that such cholesteryl ester accumulation was a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway in prostate cancer cells. Furthermore, we found that such accumulation arose from significantly enhanced uptake of exogenous lipoproteins and required cholesterol esterification. Depletion of cholesteryl ester storage significantly reduced cancer proliferation, impaired cancer invasion capability, and suppressed tumor growth in mouse xenograft models with negligible toxicity. These findings open opportunities for diagnosing and treating prostate cancer by targeting the altered cholesterol metabolism

Methodological and reporting quality in non-Cochrane systematic review updates could be improved: a comparative study

Objectives: To compare the methodological and reporting quality of updated systematic reviews (SRs) and original SRs. Study Design and Setting: We included 30 pairs of non-Cochrane updated and original SRs, identified from a search of PubMed and Embase.com. We used AMSTAR 2 to assess methodological quality and PRISMA for reporting quality. Stratified analyses were conducted to compare the differences between updated SRs and original SRs and explore factors that might affect the degree of quality change. Results: Of the 60 non-Cochrane SRs, only 2 (3.3%) were of low quality, the remaining 58 (96.7%) were of critical low quality. There were no statistically significant differences in methodological quality between the updated SRs and original SRs, although the compliance rates of 8 items of updated SRs were higher than that of original SRs. Updated SRs showed an improvement on 15 PRISMA items, but no items with statistically significant differences. The differences in fully reported AMSTAR 2 and PRISMA items between original SRs and updated SRs were also not statistically significant after adjusting for multiple review characteristics. Conclusions: The methodological and reporting quality of updated SRs were not improved compared with original SRs, although the quality could be further improved for both updated SRs and original SRs

Destabilization of Fatty Acid Synthase by Acetylation Inhibits De Novo Lipogenesis and Tumor Cell Growth

Fatty acid synthase (FASN) is the terminal enzyme in de novo lipogenesis and plays a key role in cell proliferation. Pharmacological inhibitors of FASN are being evaluated in clinical trials for treatment of cancer, obesity and other diseases. Here we report a previously unknown mechanism of FASN regulation involving its acetylation by KAT8 and its deacetylation by HDAC3. FASN acetylation promoted its degradation via the ubiquitin-proteasome pathway. FASN acetylation enhanced its association with the E3 ubiquitin-ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels. Our results suggest opportunities to target FASN acetylation as an anticancer strategy