Action video games (AVGs) have attracted increasing research attention as they offer a unique perspective into the relation between active learning and neural plasticity. However, little research has examined the relation between AVG experience and the plasticity of neural network mechanisms. It has been proposed that AVG experience is related to the integration between Salience Network (SN) and Central Executive Network (CEN), which are responsible for attention and working memory, respectively, two cognitive functions essential for AVG playing. This study initiated a systematic investigation of this proposition by analyzing AVG experts' and amateurs' resting-state brain functions through graph theoretical analyses and functional connectivity. Results reveal enhanced intra- and internetwork functional integrations in AVG experts compared to amateurs. The findings support the possible relation between AVG experience and the neural network plasticity.

Neuroimaging studies have documented that aging can disrupt certain higher cognitive systems such as the default mode network (DMN), the salience network and the central executive network (CEN). The effect of cognitive training on higher cognitive systems remains unclear. This study used a 1-year longitudinal design to explore the cognitive training effect on three higher cognitive networks in healthy older adults. The community-living healthy older adults were divided into two groups: the multi-domain cognitive training group (24 sessions of cognitive training over a 3-months period) and the wait-list control group. All subjects underwent cognitive measurements and resting-state functional magnetic resonance imaging scanning at baseline and at 1 year after the training ended. We examined training-related changes in functional connectivity (FC) within and between three networks. Compared with the baseline, we observed maintained or increased FC within all three networks after training. The scans after training also showed maintained anti-correlation of FC between the DMN and CEN compared to the baseline. These findings demonstrated that cognitive training maintained or improved the functional integration within networks and the coupling between the DMN and CEN in older adults. Our findings suggested that multi-domain cognitive training can mitigate the aging-related dysfunction of higher cognitive networks.

Lateralization of function is an important organization of the human brain. The distribution of intrinsic networks in the resting brain is strongly related to cognitive function, gender and age. In this study, a longitudinal design with 1 year's duration was used to evaluate the cognitive training effects on the lateralization of intrinsic networks among healthy older adults. The subjects were divided into two groups randomly: one with multi-domain cognitive training over 3 months and the other as a wait-list control group. Resting state fMRI data were acquired before training and 1 year after training. We analyzed the functional lateralization in 10 common resting state fMRI networks. We observed statically significant training effects on the lateralization of two important RSNs related to high-level cognition: right- and left- frontoparietal networks (FPNs). The lateralization of the left-FPN was retained especially well in the training group but decreased in the control group. The increased lateralization with aging was observed in the cerebellum network (CereN), in which the lateralization was significantly increased in the control group, although the same change tendency was observed in the training group. These findings indicate that the lateralization of the high-level cognitive intrinsic networks is sensitive to multi-domain cognitive training. This study provides neuroimaging evidence to support the hypothesis that cognitive training should have an advantage in preventing cognitive decline in healthy older adults.

Ligand-based in silico target fishing can be used to identify the potential interacting target of bioactive ligands, which is useful for understanding the polypharmacology and safety profile of existing drugs. The underlying principle of the approach is that known bioactive ligands can be used as reference to predict the targets for a new compound.

Eukaryotic translation initiation factor eIF4AI, the founding member of DEAD-box helicases, undergoes ATP hydrolysis-coupled conformational changes to unwind mRNA secondary structures during translation initiation. However, the mechanism of its coupled enzymatic activities remains unclear. Here we report that a gating mechanism for Pi release controlled by the inter-domain linker of eIF4AI regulates the coupling between ATP hydrolysis and RNA unwinding. Molecular dynamic simulations and experimental results revealed that, through forming a hydrophobic core with the conserved SAT motif of the N-terminal domain and I357 from the C-terminal domain, the linker gated the release of Pi from the hydrolysis site, which avoided futile hydrolysis cycles of eIF4AI. Further mutagenesis studies suggested this linker also plays an auto-inhibitory role in the enzymatic activity of eIF4AI, which may be essential for its function during translation initiation. Overall, our results reveal a novel regulatory mechanism that controls eIF4AI-mediated mRNA unwinding and can guide further mechanistic studies on other DEAD-box helicases.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by motor and nonmotor signs and symptoms. To date, many studies of PD have focused on its cardinal motor symptoms. To study the nonmotor signs of early PD, we investigated the reactions solicited by heat pain stimuli in early untreated PD patients without pain using fMRI. The activation patterns of contact heat stimuli (51°C) were assessed in 14 patients and 17 age- and sex-matched healthy controls. Patients with PD showed significant decreases in activation of the superior temporal gyrus (STG) and insula compared with controls. In addition, a significant relationship between activation of the insula and STG and the pain scores was observed in healthy controls but not in PD. This study provided further support that the insula and STG are important parts of the somatosensory circuitry recruited during the period of pain. The hypoactivity of the STG and insula in PD implied that functions including affective, cognitive, and sensory-discriminative processes, which are associated with the insula and STG, were disturbed. This finding supports the view that leaving early PD untreated could be tied directly to central nervous system dysfunction.

MAGEA10, a cancer/testis antigens expressed in tumors but not in normal tissues with the exception of testis and placenta, represents an attractive target for cancer immunotherapy. However, suppressive cytoenvironment and requirement of specific HLA-alleles presentation frequently led to immunotherapy failure. In this study MAGEA10 was scarcely expressed in cancer patients, but enhanced by viili polysaccharides, which indicates a possibility of increasing epitopes presentation. Furthermore the correlation of gene expression with methylation, indicated by R(2) value for MAGEA10 that was 3 times higher than the value for other MAGE genes tested, provides an explanation of why MAGEA10 was highly inhibited, this is also seen by Kaplan-Meier analysis because MAGEA10 did not change the patients' lifespan. By using Molecular-Docking method, 3 MAGEA10 peptides were found binding to the groove position of HLA-A(∗)0210 as same as MAGEA4 peptide co-crystallized with HLA-A(∗)0210, which indicates that they could be promising for HLA-A(∗)0201 presentation in immunotherapy.

Plant sterols (PS) have potential preventive function in atherosclerosis due to their cholesterol-lowering ability. Dietary α-linolenic acid in flaxseed oil is associated with a reduction in cardiovascular events through its hypolipidemic and anti-inflammation properties. This study was designed to evaluate the effects of flaxseed oil containing α-linolenic acid ester of PS (ALA-PS) on atherosclerosis and investigate the underlying mechanisms. C57BL/6 mice were administered a regular diet and apoE knockout (apoE-KO) mice were given a high fat diet alone or supplemented with 5% flaxseed oil with or without 3.3% ALA-PS for 18 weeks. Results demonstrated that flaxseed oil containing ALA-PS was synergistically interaction in ameliorating atherosclerosis as well as optimizing overall lipid levels, inhibiting inflammation and reducing oxidative stress. These data were associated with the modification effects on expression levels of genes involved in lipid metabolism (PPARα, HMGCR, and SREBPs), inflammation (IL-6, TNF, MCP-1, and VCAM-1), and oxidative stress (NADPH oxidase).

Brain imaging studies have revealed that functional and structural brain connectivity in the so-called triple network (i.e., default mode network (DMN), salience network (SN) and central executive network (CEN)) are consistently altered in schizophrenia. However, similar changes have also been found in patients with major depressive disorder, prompting the question of specific triple network signatures for the two disorders. In this study, we proposed Supervised Convex Nonnegative Matrix Factorization (SCNMF) to extract distributed multi-modal brain patterns. These patterns distinguish schizophrenia and major depressive disorder in a latent low-dimensional space of the triple brain network. Specifically, 21 patients of schizophrenia and 25 patients of major depressive disorder were assessed by T1-weighted, diffusion-weighted, and resting-state functional MRIs. Individual structural and functional connectivity networks, based on pre-defined regions of the triple network were constructed, respectively. Afterwards, SCNMF was employed to extract the discriminative patterns. Experiments indicate that SCNMF allows extracting the low-rank discriminative patterns between the two disorders, achieving a classification accuracy of 82.6% based on the extracted functional and structural abnormalities with support vector machine. Experimental results show the specific brain patterns for schizophrenia and major depressive disorder that are multi-modal, complex, and distributed in the triple network. Parts of the prefrontal cortex including superior frontal gyri showed variation between patients with schizophrenia and major depression due to structural properties. In terms of functional properties, the middle cingulate cortex, inferior parietal lobule, and cingulate cortex were the most discriminative regions.

Cerebral palsy (CP) has long been investigated to be associated with a range of motor and cognitive dysfunction. As the two most common CP subtypes, spastic cerebral palsy (SCP) and dyskinetic cerebral palsy (DCP) may share common and distinct elements in their pathophysiology. However, the common and distinct dysfunctional characteristics between SCP and DCP on the brain network level are less known. This study aims to detect the alteration of brain functional connectivity in children with SCP and DCP based on resting-state functional MRI (fMRI). Resting-state networks (RSNs) were established based on the independent component analysis (ICA), and the functional network connectivity (FNC) was performed on the fMRI data from 16 DCP, 18 bilateral SCP, and 18 healthy children. Compared with healthy controls, altered functional connectivity within the cerebellum network, sensorimotor network (SMN), left frontoparietal network (LFPN), and salience network (SN) were found in DCP and SCP groups. Furthermore, the disconnections of the FNC consistently focused on the visual pathway; covariance of the default mode network (DMN) with other networks was observed both in DCP and SCP groups, while the DCP group had a distinct connectivity abnormality in motor pathway and self-referential processing-related connections. Correlations between the functional disconnection and the motor-related clinical measurement in children with CP were also found. These findings indicate functional connectivity impairment and altered integration widely exist in children with CP, suggesting that the abnormal functional connectivity is a pathophysiological mechanism of motor and cognitive dysfunction of CP.

Cushing's disease results from corticotroph adenomas of the pituitary that hypersecrete adrenocorticotropin (ACTH), leading to excess glucocorticoid and hypercortisolism. Mutations of the deubiquitinase gene USP8 occur in 35-62% of corticotroph adenomas. However, the major driver mutations in USP8 wild-type tumors remain elusive. Here, we report recurrent mutations in the deubiquitinase gene USP48 (predominantly encoding p.M415I or p.M415V; 21/91 subjects) and BRAF (encoding p.V600E; 15/91 subjects) in corticotroph adenomas with wild-type USP8. Similar to USP8 mutants, both USP48 and BRAF mutants enhance the promoter activity and transcription of the gene encoding proopiomelanocortin (POMC), which is the precursor of ACTH, providing a potential mechanism for ACTH overproduction in corticotroph adenomas. Moreover, primary corticotroph tumor cells harboring BRAF V600E are sensitive to the BRAF inhibitor vemurafenib. Our study thus contributes to the understanding of the molecular mechanism of the pathogenesis of corticotroph adenoma and informs therapeutic targets for this disease.

Th17 cells have been reported to produce proinflammatory cytokines like Interleukin-17, IL-22, and regarded as important players in various inflammatory diseases. One of the IL-12 cytokine family cytokines, IL-23, composed of p19 and p40 subunit, is known for its potential to promote Th17 development and IL-17 producing, and the IL-23/IL-17 pathway is considered to be potential therapeutic target for autoimmune inflammation responses. Knockout mice deficient in either IL-23 or IL-17 related genes can suppress the allergic responses. Several IL-23 or IL-17 neutralizing agents are being evaluated in vitro or in vivo to disrupt the IL-23/IL-17 axis. Herein, we report that prokaryotically expressed soluble IL-23 receptor cytokine-binding homology region as an endogenous extracellular receptor analogue could be a natural antagonist against IL-23/IL-17 axis. We provide evidence that IL23R-CHR can bind to IL-23 in a dose-dependent manner in vitro, and block IL-23 signal by IL23R-CHR reducing the RORγt expression, which in turn lowers the expression of IL-17/IL-22, thus protecting naive CD4+ T cells against Th17 development. Together, this study indicates the importance of IL-23 pathway in Th17 development and the negative regulation of Th17 development by IL23R-CHR, and highlights the important roles of the soluble receptor extracellular region in the therapeutic strategy of neutralizing IL-23.

Although interleukin 1 (IL-1) induces expression of the transcription factor IRF1 (interferon-regulatory factor 1), the roles of IRF1 in immune and inflammatory responses and mechanisms of its activation remain elusive. Here we found that IRF1 was essential for IL-1-induced expression of the chemokines CXCL10 and CCL5, which recruit mononuclear cells into sites of sterile inflammation. Newly synthesized IRF1 acquired Lys63 (K63)-linked polyubiquitination mediated by the apoptosis inhibitor cIAP2 that was enhanced by the bioactive lipid S1P. In response to IL-1, cIAP2 and the sphingosine kinase SphK1 (the enzyme that generates S1P) formed a complex with IRF1, which led to its activation. Thus, IL-1 triggered a hitherto unknown signaling cascade that controlled the induction of IRF1-dependent genes that encode molecules important for sterile inflammation.

The structural connection patterns of the human brain are the underlying bases for functional connectivity. Although abnormal functional connectivity has been uncovered in childhood absence epilepsy (CAE) in previous electroencephalography and functional magnetic resonance imaging studies, little is known regarding the structural connectivity in CAE. We hypothesized that the structural connectivity would be disrupted in response to the decreased brain function in CAE.

Bruton's tyrosine kinase contains a pleckstrin homology domain, and it specifically binds inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4), which is involved in the maturation of B cells. In this paper, we studied 12 systems including the wild type and 11 mutants, K12R, S14F, K19E, R28C/H, E41K, L11P, F25S, Y40N, and K12R-R28C/H, to investigate any change in the ligand binding site of each mutant. Molecular dynamics simulations combined with the method of molecular mechanics/Poisson-Boltzmann solvent-accessible surface area have been applied to the twelve systems, and reasonable mutant structures and their binding free energies have been obtained as criteria in the final classification. As a result, five structures, K12R, K19E, R28C/H, and E41K mutants, were classified as "functional mutations," whereas L11P, S14F, F25S, and Y40N were grouped into "folding mutations." This rigorous study of the binding affinity of each of the mutants and their classification provides some new insights into the biological function of the Btk-PH domain and related mutation-causing diseases.

Musicians experience a large amount of information transfer and integration of complex sensory, motor, and auditory processes when training and playing musical instruments. Therefore, musicians are a useful model in which to investigate neural adaptations in the brain.

MicroRNAs (miRNAs) are potential regulators that contribute to the pathogenesis of cancer. Microarray technologies have been widely used to characterize aberrant miRNA expression patterns in cancer. Nevertheless, the miRNAs expression signatures identified for a same cancer differs among laboratories due to the cancer heterogeneity. In addition, how the deregulated miRNAs coordinately contribute to the tumourigenic process of prostate cancer remains elusive.

Yougui pills (YGPs) have been used for centuries in the treatment of Chinese patients with Kidney-Yang Deficiency Syndrome. Despite the fact that the efficiency of YGPs on treating osteoarthritis has been verified in clinic, the underlying mechanisms are not totally understood. The present study observes the therapeutic role of YGPs and mechanisms underlying its chondroprotective action in osteoarthritic cartilage. To evaluate the chondroprotective effects of YGPs, we examined the impact of orally administered YGPs in a model of destabilization of the medial meniscus (DMM). Male C57BL/6J mice were provided a daily treatment of YGPs and a DMM surgery was performed on the right knee. At 12 weeks post-surgery, the joints were harvested for tissue analyses, including histomorphometry, OARSI scoring, micro-CT and immunohistochemistry for COL-2, MMP-13 and pSMAD-2. We also performed the relative experiments mentioned above in mice with Tgfbr2 conditional knockout (TGF-βRIICol2ER mice) in articular cartilage. To evaluate the safety of YGPs, hematology was determined in each group. Amelioration of cartilage degradation was observed in the YGPs group, with increases in cartilage area and thickness, proteoglycan matrix, and decreases in OARSI score at 12 weeks post surgery. In addition, reduced BV/TV and Tb. Th, and elevated Tb. Sp were observed in DMM-induced mice followed by YGPs treatment. Moreover, the preservation of cartilage correlated with reduced MMP-13, and elevated COL-2 and pSMAD-2 protein expressional levels were also revealed in DMM-induced mice treated with YGPs. Similarly, TGF-βRIICol2ER mice exhibited significant OA-like phenotype. However, no significant difference in cartilage structure was observed in TGF-βRIICol2ER mice after YGPs treatment. Interestingly, no obvious adverse effects were observed in mice from each group based on the hematologic analyses. These findings suggested that YGPs could inhibit cartilage degradation through enhancing TGF-β/Smad signaling activation, and be considered a good option for the treatment of osteoarthritis.

CLYBL encodes a ubiquitously expressed mitochondrial enzyme, conserved across all vertebrates, whose cellular activity and pathway assignment are unknown. Its homozygous loss is tolerated in seemingly healthy individuals, with reduced circulating B12 levels being the only and consistent phenotype reported to date. Here, by combining enzymology, structural biology, and activity-based metabolomics, we report that CLYBL operates as a citramalyl-CoA lyase in mammalian cells. Cells lacking CLYBL accumulate citramalyl-CoA, an intermediate in the C5-dicarboxylate metabolic pathway that includes itaconate, a recently identified human anti-microbial metabolite and immunomodulator. We report that CLYBL loss leads to a cell-autonomous defect in the mitochondrial B12 metabolism and that itaconyl-CoA is a cofactor-inactivating, substrate-analog inhibitor of the mitochondrial B12-dependent methylmalonyl-CoA mutase (MUT). Our work de-orphans the function of human CLYBL and reveals that a consequence of exposure to the immunomodulatory metabolite itaconate is B12 inactivation.

Severe acute respiratory syndrome coronavirus (SARS-CoV) is responsible for SARS infection. Nucleocapsid protein (NP) of SARS-CoV (SARS_NP) functions in enveloping the entire genomic RNA and interacts with viron structural proteins, thus playing important roles in the process of virus particle assembly and release. Protein-protein interaction analysis using bioinformatics tools indicated that SARS_NP may bind to human cyclophilin A (hCypA), and surface plasmon resonance (SPR) technology revealed this binding with the equilibrium dissociation constant ranging from 6 to 160nM. The probable binding sites of these two proteins were detected by modeling the three-dimensional structure of the SARS_NP-hCypA complex, from which the important interaction residue pairs between the proteins were deduced. Mutagenesis experiments were carried out for validating the binding model, whose correctness was assessed by the observed effects on the binding affinities between the proteins. The reliability of the binding sites derived by the molecular modeling was confirmed by the fact that the computationally predicted values of the relative free energies of the binding for SARS_NP (or hCypA) mutants to the wild-type hCypA (or SARS_NP) are in good agreement with the data determined by SPR. Such presently observed SARS_NP-hCypA interaction model might provide a new hint for facilitating the understanding of another possible SARS-CoV infection pathway against human cell.