miRNA-378 reverses chemoresistance to cisplatin in lung adenocarcinoma cells by targeting secreted clusterin

Cisplatin resistance is a major obstacle in the treatment of NSCLC, and its mechanism has not been fully elucidated. The objectives of the study were to determine the role of miR-378 in the sensitivity of lung adenocarcinoma cells to cisplatin (cDDP) and its working mechanism. With TargetScan and luciferase assay, miR-378 was found to directly target sCLU. miR-378 and sCLU were regulated in A549/cDDP and Anip973/cDDP cells to investigate the effect of miR-378 on the sensitivity and apoptotic effects of cDDP. The effect of miR-378 upregulation on tumor growth was analyzed in a nude mouse xenograft model. The correlation between miR-378 and chemoresistance was tested in patient samples. We found that upregulation of miR-378 in A549/cDDP and Anip973/cDDP cells significantly down-regulated sCLU expression, and sensitized these cells to cDDP. miR-378 overexpression inhibited tumor growth and sCLU expression in a xenograft animal model. Analysis of human lung adenocarcinoma tissues revealed that the cDDP sensitive group expressed higher levels of miR-378 and lower levels of sCLU. miR-378 and sCLU were negatively correlated. To conclude, we identified sCLU as a novel miR-378 target, and we showed that targeting sCLU via miR-378 may help disable the chemoresistance against cisplatin in lung adenocarcinoma cells

The impact of cognitive training on cerebral white matter in community-dwelling elderly : one-year prospective longitudinal diffusion tensor imaging study

It has been shown that cognitive training (CogTr) is effective and recuperative for older adults, and can be used to fight against cognitive decline. In this study, we investigated whether behavioural gains from CogTr would extend to white matter (WM) microstructure, and whether training-induced changes in WM integrity would be associated with improvements in cognitive function, using diffusion tensor imaging (DTI). 48 healthy community elderly were either assigned to multi-domain or single-domain CogTr groups to receive 24 sessions over 12 weeks, or to a control group. DTI was performed at both baseline and 12-month follow-up. Positive effects of multi-domain CogTr on long-term changes in DTI indices were found in posterior parietal WM. Participants in the multi-domain group showed a trend of long-term decrease in axial diffusivity (AD) without significant change in fractional anisotropy (FA), mean diffusivity (MD) or radial diffusivity (RD), while those in the control group displayed a significant FA decrease, and an increase in MD and RD. In addition, significant relationships between an improvement in processing speed and changes in RD, MD and AD were found in the multi-domain group. These findings support the hypothesis that plasticity of WM can be modified by CogTr, even in late adulthood

Structural Basis for Recognition of Human Enterovirus 71 by a Bivalent Broadly Neutralizing Monoclonal Antibody

Enterovirus 71 (EV71) is the main pathogen responsible for hand, foot and mouth disease with severe neurological complications and even death in young children. We have recently identified a highly potent anti-EV71 neutralizing monoclonal antibody, termed D5. Here we investigated the structural basis for recognition of EV71 by the antibody D5. Four three-dimensional structures of EV71 particles in complex with IgG or Fab of D5 were reconstructed by cryo-electron microscopy (cryo-EM) single particle analysis all at subnanometer resolutions. The most critical EV71 mature virion-Fab structure was resolved to a resolution of 4.8 Å, which is rare in cryo-EM studies of virus-antibody complex so far. The structures reveal a bivalent binding pattern of D5 antibody across the icosahedral 2-fold axis on mature virion, suggesting that D5 binding may rigidify virions to prevent their conformational changes required for subsequent RNA release. Moreover, we also identified that the complementary determining region 3 (CDR3) of D5 heavy chain directly interacts with the extremely conserved VP1 GH-loop of EV71, which was validated by biochemical and virological assays. We further showed that D5 is indeed able to neutralize a variety of EV71 genotypes and strains. Moreover, D5 could potently confer protection in a mouse model of EV71 infection. Since the conserved VP1 GH-loop is involved in EV71 binding with its uncoating receptor, the scavenger receptor class B, member 2 (SCARB2), the broadly neutralizing ability of D5 might attribute to its inhibition of EV71 from binding SCARB2. Altogether, our results elucidate the structural basis for the binding and neutralization of EV71 by the broadly neutralizing antibody D5, thereby enhancing our understanding of antibody-based protection against EV71 infection. © 2016 Ye et al

Microstructure abnormalities of the diffusion quantities in children with attention-deficit/hyperactivity disorder: an AFQ and TBSS study

ObjectiveTo explore the specific alterations of white matter microstructure in children with attention-deficit/hyperactivity disorder (ADHD) by automated fiber quantification (AFQ) and tract-based spatial statistics (TBSS), and to analyze the correlation between white matter abnormality and impairment of executive function.MethodsIn this prospective study, a total of twenty-seven patients diagnosed with ADHD (20 males, 7 females; mean age of 8.89 ± 1.67 years) and twenty-two healthy control (HC) individuals (11 males, 11 females, mean age of 9.82 ± 2.13 years) were included. All participants were scanned with diffusion kurtosis imaging (DKI) and assessed for executive functions. AFQ and TBSS analysis methods were used to investigate the white matter fiber impairment of ADHD patients, respectively. Axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD) and fractional anisotropy (FA) of 17 fiber properties were calculated using the AFQ. The mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), mean diffusivity (MDDKI), axial diffusivity (ADDKI), radial diffusivity (RDDKI) and fractional anisotropy (FADKI) of DKI and AD, RD, MD, and FA of diffusion tensor imaging (DTI) assessed the integrity of the white matter based on TBSS. Partial correlation analyses were conducted to evaluate the correlation between white matter abnormalities and clinical test scores in ADHD while taking age, gender, and education years into account. The analyses were all family-wise error rate (FWE) corrected.ResultsADHD patients performed worse on the Behavior Rating Inventory of Executive Function (BRIEF) test (p < 0.05). Minor variances existed in gender and age between ADHD and HC, but these variances did not yield statistically significant distinctions. There were no significant differences in TBSS for DKI and DTI parameters (p > 0.05, TFCE-corrected). Compared to HC volunteers, the mean AD value of right cingulum bundle (CB_R) fiber tract showed a significantly higher level in ADHD patients following the correction of FWE. As a result of the point-wise comparison between groups, significant alterations (FWE correction, p < 0.05) were mainly located in AD (nodes 36–38, nodes 83–97) and MD (nodes 92–95) of CB_R. There was no significant correlation between white matter diffusion parameters and clinical test scores in ADHD while taking age, gender, and education years into account.ConclusionThe AFQ method can detect ADHD white matter abnormalities in a specific location with greater sensitivity, and the CB_R played a critical role. Our findings may be helpful in further studying the relationship between focal white matter abnormalities and ADHD

Viral Diversity and Its Relationship With Environmental Factors at the Surface and Deep Sea of Prydz Bay, Antarctica

A viral metagenomic analysis of five surface and two bottom water (878 meters below surface, mbs, and 3,357 mbs) samples from Prydz Bay, was conducted during February–March 2015. The results demonstrated that most of the DNA viruses were dsDNA viruses (79.73–94.06%, except at PBI1, 37.51%). Of these, Caudovirales (Siphoviridae, Myoviridae, and Podoviridae) phages were most abundant in surface seawater (67.67–71.99%), while nucleocytoplasmic large DNA viruses (NCLDVs) (Phycodnaviridae, Mimiviridae, and Pandoraviridae accounted for >30% of dsDNA viruses) were most abundant in the bottom water (3,357 mbs). Of the ssDNA viruses, Microviridae was the dominant family in PBI2, PBI3, PBOs, and PBI4b (57.09–87.55%), while Inoviridae (58.16%) was the dominant family in PBI1. Cellulophaga phages (phi38:1 and phi10:1) and Flavobacterium phage 11b, infecting the possible host strains affiliated with the family Flavobacteriaceae of the phylum Bacteroidetes, were abundant in surface water dsDNA viromes. The long contig (PBI2_1_C) from the viral metagenomes were most similar to the genome architectures of Cellulophaga phage phi10:1 and Flavobacterium phage 11b from the Arctic Ocean. Comparative analysis showed that the surface viral community of Prydz Bay could be clearly separated from other marine and freshwater environments. The deep sea viral community was similar to the deep sea viral metagenome at A Long-term Oligotrophic Habitat Assessment Station (ALOHA, at 22°45′N, 158°00′W). The multivariable analysis indicated that nutrients probably played an important role in shaping the local viral community structure. This study revealed the preliminary characteristics of the viral community in Prydz Bay, from both the surface and the deep sea. It provided evidence of the relationships between the virome and the environment in Prydz Bay and provided the first data from the deep sea viral community of the Southern Ocean

A branched chain amino acid metabolite drives vascular transport of fat and causes insulin resistance

Epidemiological and experimental data implicate branched chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms underlying this link remain unclear.1–3 Insulin resistance in skeletal muscle stems from excess accumulation of lipid species4, a process that requires blood-borne lipids to first traverse the blood vessel wall. Little is known, however, of how this trans-endothelial transport occurs or is regulated. Here, we leverage PGC-1α, a transcriptional coactivator that regulates broad programs of FA consumption, to identify 3-hydroxy-isobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a novel paracrine regulator of trans-endothelial fatty acids (FA) transport. 3-HIB is secreted from muscle cells, activates endothelial FA transport, stimulates muscle FA uptake in vivo, and promotes muscle lipid accumulation and insulin resistance in animals. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the promotion of endothelial FA uptake. 3-HIB levels are elevated in muscle from db/db mice and from subjects with diabetes. These data thus unveil a novel mechanism that regulates trans-endothelial flux of FAs, revealing 3-HIB as a new bioactive signaling metabolite that links the regulation of FA flux to BCAA catabolism and provides a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes

Analysis and control of a parallel lower limb based on pneumatic artificial muscles

Most robots that are actuated by antagonistic pneumatic artificial muscles are controlled by various control algorithms that cannot adequately imitate the actual muscle distribution of human limbs. Other robots in which the distribution of pneumatic artificial muscle is similar to that of human limbs can only analyze the position of the robot using perceptual data instead of rational knowledge. In order to better imitate the movement of a human limb, the article proposes a humanoid lower limb in the form of a parallel mechanism where muscle is unevenly distributed. Next, the kinematic and dynamic movements of bionic hip joint are analyzed, where the joint movement is controlled by an observer-based fuzzy adaptive control algorithm as a whole rather than each individual pneumatic artificial muscle and parameters that are optimized by a neural network. Finally, experimental results are provided to confirm the effectiveness of the proposed method. We also document the role of muscle in trajectory tracking for the piriformis and musculi obturator internus in isobaric processes