Electroencephalographic interbrain synchronization in children with disabilities, their parents, and neurologic music therapists

: As with typically developing children, children with cerebral palsy and autism spectrum disorder develop important socio-emotional rapport with their parents and healthcare providers. However, the neural mechanisms underlying these relationships have been less studied. By simultaneously measuring the brain activity of multiple individuals, interbrain synchronization could serve as a neurophysiological marker of social-emotional responses. Music evokes emotional and physiological responses and enhances social cohesion. These characteristics of music have fostered its deployment as a therapeutic medium in clinical settings. Therefore, this study investigated two aspects of interbrain synchronization, namely, its phase and directionality, in child-parent (CP) and child-therapist (CT) dyads during music and storytelling sessions (as a comparison). A total of 17 participants (seven cerebral palsy or autism spectrum disorder children [aged 12-18 years], their parents, and three neurologic music therapists) completed this study, comprising seven CP and seven CT dyads. Each music therapist worked with two or three children. We found that session type, dyadic relationship, frequency band, and brain region were significantly related to the degree of interbrain synchronization and its directionality. Particularly, music sessions and CP dyads were associated with higher interbrain synchronization and stronger directionality. Delta (.5-4 Hz) range showed the highest phase locking value in both CP and CT dyads in frontal brain regions. It appears that synchronization is directed predominantly from parent to child, that is, parents and music therapists' brain activity tended to influence a child's. Our findings encourage further research into neural synchrony in children with disabilities, especially in musical contexts, and its implications for social and emotional development

The Multiscale Backbone of the Human Phenotype Network Based on Biological Pathways

Background: Networks are commonly used to represent and analyze large and complex systems of interacting elements. In systems biology, human disease networks show interactions between disorders sharing common genetic background. We built pathway-based human phenotype network (PHPN) of over 800 physical attributes, diseases, and behavioral traits; based on about 2,300 genes and 1,200 biological pathways. Using GWAS phenotype-to-genes associations, and pathway data from Reactome, we connect human traits based on the common patterns of human biological pathways, detecting more pleiotropic effects, and expanding previous studies from a gene-centric approach to that of shared cell-processes. Results: The resulting network has a heavily right-skewed degree distribution, placing it in the scale-free region of the network topologies spectrum. We extract the multi-scale information backbone of the PHPN based on the local densities of the network and discarding weak connection. Using a standard community detection algorithm, we construct phenotype modules of similar traits without applying expert biological knowledge. These modules can be assimilated to the disease classes. However, we are able to classify phenotypes according to shared biology, and not arbitrary disease classes. We present examples of expected clinical connections identified by PHPN as proof of principle. Conclusions: We unveil a previously uncharacterized connection between phenotype modules and discuss potential mechanistic connections that are obvious only in retrospect. The PHPN shows tremendous potential to become a useful tool both in the unveiling of the diseases’ common biology, and in the elaboration of diagnosis and treatments

Simvastatin inhibits TLR8 signaling in primary human monocytes and spontaneous TNF production from rheumatoid synovial membrane cultures

Simvastatin has been shown to have anti-inflammatory effects that are independent of its serum cholesterol lowering action, but the mechanisms by which these anti-inflammatory effects are mediated have not been elucidated. To explore the mechanism involved, the effect of simvastatin on Toll-like receptor (TLR) signalling in primary human monocytes was investigated. A short pre-treatment with simvastatin dose-dependently inhibited the production of tumor necrosis factor-α (TNF) in response to TLR8 (but not TLRs 2, 4, or 5) activation. Statins are known inhibitors of the cholesterol biosynthetic pathway, but intriguingly TLR8 inhibition could not be reversed by addition of mevalonate or geranylgeranyl pyrophosphate; downstream products of cholesterol biosynthesis. TLR8 signalling was examined in HEK 293 cells stably expressing TLR8, where simvastatin inhibited IKKα/β phosphorylation and subsequent NF-κB activation without affecting the pathway to AP-1. Since simvastatin has been reported to have anti-inflammatory effects in RA patients and TLR8 signalling contributes to TNF production in human RA synovial tissue in culture, simvastatin was tested in these cultures. Simvastatin significantly inhibited the spontaneous release of TNF in this model which was not reversed by mevalonate. Together, these results demonstrate a hitherto unrecognized mechanism of simvastatin inhibition of TLR8 signalling that may in part explain its beneficial anti-inflammatory effects

Swine ANP32A supports avian influenza virus polymerase

Avian influenza viruses occasionally infect and adapt to mammals, including humans. Swine are often described as 'mixing vessels', being susceptible to both avian and human origin viruses, which allows the emergence of novel reassortants, such as the precursor to the 2009 H1N1 pandemic. ANP32 proteins are host factors that act as influenza virus polymerase cofactors. In this study we describe how swine ANP32A, uniquely among the mammalian ANP32 proteins tested, supports activity of avian origin influenza virus polymerases, and avian influenza virus replication. We further show that after the swine-origin influenza virus emerged in humans and caused the 2009 pandemic it evolved polymerase gene mutations that enabled it to more efficiently use human ANP32 proteins. We map the enhanced pro-viral activity of swine ANP32A to a pair of amino acids, 106 and 156, in the leucine-rich repeat and central domains and show these mutations enhance binding to influenza virus trimeric polymerase. These findings help elucidate the molecular basis for the 'mixing vessel' trait of swine and further our understanding of the evolution and ecology of viruses in this host.Importance Avian influenza viruses can jump from wild birds and poultry into mammalian species such as humans or swine, but only continue to transmit if they accumulate mammalian adapting mutations. Pigs appear uniquely susceptible to both avian and human strains of influenza and are often described as virus 'mixing vessels'. In this study, we describe how a host factor responsible for regulating virus replication, ANP32A, is different between swine and humans. Swine ANP32A allows a greater range of influenza viruses, specifically those from birds, to replicate. It does this through binding the virus polymerase more tightly than the human version of the protein. This work helps to explain the unique properties of swine as 'mixing vessels'

Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): Randomized clinical trial

Objective: To determine whether low intensity pulsed ultrasound (LIPUS), compared with sham treatment, accelerates functional recovery and radiographic healing in patients with operatively managed tibial fractures. Design: A concealed, randomized, blinded, sham controlled clinical trial with a parallel group design of 501 patients, enrolled between October 2008 and September 2012, and followed for one year. Setting: 43 North American academic trauma centers. Participants: Skeletally mature men or women with an open or closed tibial fracture amenable to intramedullary nail fixation. Exclusions comprised pilon fractures, tibial shaft fractures that extended into the joint and required reduction, pathological fractures, bilateral tibial fractures, segmental fractures, spiral fractures \u3e7.5 cm in length, concomitant injuries that were likely to impair function for at least as long as the patient\u27s tibial fracture, and tibial fractures that showed 1 cm gap after surgical fixation. 3105 consecutive patients who underwent intramedullary nailing for tibial fracture were assessed, 599 were eligible and 501 provided informed consent and were enrolled. Interventions: Patients were allocated centrally to self administer daily LIPUS (n=250) or use a sham device (n=251) until their tibial fracture showed radiographic healing or until one year after intramedullary fixation. Main outcom e measures: Primary registry specified outcome was time to radiographic healing within one year of fixation; secondary outcome was rate of non-union. Additional protocol specified outcomes included short form-36 (SF-36) physical component summary (PCS) scores, return to work, return to household activities, return to ≥80% of function before injury, return to leisure activities, time to full weight bearing, scores on the health utilities index (mark 3), and adverse events related to the device. Results: SF-36 PCS data were acquired from 481/501 (96%) patients, for whom we had 2303/2886 (80%) observations, and radiographic healing data were acquired from 482/501 (96%) patients, of whom 82 were censored. Results showed no impact on SF-36 PCS scores between LIPUS and control groups (mean difference 0.55, 95% confidence interval -0.75 to 1.84; P=0.41) or for the interaction between time and treatment (P=0.30); minimal important difference is 3-5 points) or in other functional measures. There was also no difference in time to radiographic healing (hazard ratio 1.07, 95% confidence interval 0.86 to 1.34; P=0.55). There were no differences in safety outcomes between treatment groups. Patient compliance was moderate; 73% of patients administered ≥50% of all recommended treatments. Conclusions: Postoperative use of LIPUS after tibial fracture fixation does not accelerate radiographic healing and fails to improve functional recovery. Study registration: ClinicalTrialGov Identifier: NCT00667849

CD44v6 Regulates Growth of Brain Tumor Stem Cells Partially through the AKT-Mediated Pathway

Identification of stem cell-like brain tumor cells (brain tumor stem-like cells; BTSC) has gained substantial attention by scientists and physicians. However, the mechanism of tumor initiation and proliferation is still poorly understood. CD44 is a cell surface protein linked to tumorigenesis in various cancers. In particular, one of its variant isoforms, CD44v6, is associated with several cancer types. To date its expression and function in BTSC is yet to be identified. Here, we demonstrate the presence and function of the variant form 6 of CD44 (CD44v6) in BTSC of a subset of glioblastoma multiforme (GBM). Patients with CD44high GBM exhibited significantly poorer prognoses. Among various variant forms, CD44v6 was the only isoform that was detected in BTSC and its knockdown inhibited in vitro growth of BTSC from CD44high GBM but not from CD44low GBM. In contrast, this siRNA-mediated growth inhibition was not apparent in the matched GBM sample that does not possess stem-like properties. Stimulation with a CD44v6 ligand, osteopontin (OPN), increased expression of phosphorylated AKT in CD44high GBM, but not in CD44low GBM. Lastly, in a mouse spontaneous intracranial tumor model, CD44v6 was abundantly expressed by tumor precursors, in contrast to no detectable CD44v6 expression in normal neural precursors. Furthermore, overexpression of mouse CD44v6 or OPN, but not its dominant negative form, resulted in enhanced growth of the mouse tumor stem-like cells in vitro. Collectively, these data indicate that a subset of GBM expresses high CD44 in BTSC, and its growth may depend on CD44v6/AKTpathway

Participation of annexin 1 in the response of Arabidopsis thaliana to lead exposure: potential for phytoremediation

Heavy metal pollution has become a serious public health and environmental concern. Lead (Pb) is one of the heavy metals known to bioaccumulate in plants. Phytoremediation is an emerging technology based on the ability of green plants to remove Pb from the environment in a cost-efficient and ecologically sound manner. Currently, an important research focus is to seek a better understanding of the mechanisms of Pb tolerance by plant cells, with the aim of genetically engineering plants with improved tolerance to Pb, and hence better phytoremediation capabilities in the near future. Annexin, a calcium-dependent membrane-binding protein is believed to play a role in many essential cellular processes. It has been shown that expression of annexin genes from Arabidopsis thaliana are differentially regulated in response to a variety of abiotic stresses. Thus annexins are likely be involved in the response of plants to heavy metal stress. This study aimed to obtain new insights into whether annexin 1 (AnnAt1), is involved in Pb tolerance in plant cells. Message levels of AnnAt1 were assessed in response to Pb treatments using quantitative real-time PCR. Expression results were analysed using REST 2008 and normalized against the mitosis protein YLS8. We found that Pb effect on AnnAt1 expression in plants exposed to lower Pb concentrations (25 µM, 50 µM, and 75 µM) was not significantly different from the controls. However, AnnAt1 message levels doubled (2.12-fold, S.E. range is 1.77 - 2.61, p < 0.001) in seedlings treated with 100 µM Pb, in comparison to the control plants. The relative contribution of AnnAt1 in defence against Pb stress will be discussed

Potential Risks of Excess Iodine Ingestion and Exposure: Statement by the American Thyroid Association Public Health Committee

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140261/1/thy.2014.0331.pd

Cosmic Bell Test using Random Measurement Settings from High-Redshift Quasars

In this Letter, we present a cosmic Bell experiment with polarization-entangled photons, in which measurement settings were determined based on real-time measurements of the wavelength of photons from high-redshift quasars, whose light was emitted billions of years ago, the experiment simultaneously ensures locality. Assuming fair sampling for all detected photons and that the wavelength of the quasar photons had not been selectively altered or previewed between emission and detection, we observe statistically significant violation of Bell's inequality by $9.3$ standard deviations, corresponding to an estimated $p$ value of $\lesssim 7.4 \times 10^{-21}$. This experiment pushes back to at least $\sim 7.8$ Gyr ago the most recent time by which any local-realist influences could have exploited the "freedom-of-choice" loophole to engineer the observed Bell violation, excluding any such mechanism from $96\%$ of the space-time volume of the past light cone of our experiment, extending from the big bang to today.Comment: 9 pages, 4 figures, plus Supplemental Material (16 pages, 8 figures). Matches version to be published in Physical Review Letter

Laser microdissection and mass spectrometry–based proteomics aids the diagnosis and typing of renal amyloidosis

Accurate diagnosis and typing of renal amyloidosis is critical for prognosis, genetic counseling, and treatment. Laser microdissection and mass spectrometry are emerging techniques for the analysis and diagnosis of many renal diseases. Here we present the results of laser microdissection and mass spectrometry performed on 127 cases of renal amyloidosis during 2008–2010. We found the following proteins in the amyloid deposits: immunoglobulin light and heavy chains, secondary reactive serum amyloid A protein, leukocyte cell–derived chemotaxin-2, fibrinogen-α chain, transthyretin, apolipoprotein A-I and A-IV, gelsolin, and β-2 microglobulin. Thus, laser microdissection of affected areas within the kidney followed by mass spectrometry provides a direct test of the composition of the deposit and forms a useful ancillary technique for the accurate diagnosis and typing of renal amyloidosis in a single procedure