The cross-frequency mediation mechanism of intracortical information transactions

In a seminal paper by von Stein and Sarnthein (2000), it was hypothesized that "bottom-up" information processing of "content" elicits local, high frequency (beta-gamma) oscillations, whereas "top-down" processing is "contextual", characterized by large scale integration spanning distant cortical regions, and implemented by slower frequency (theta-alpha) oscillations. This corresponds to a mechanism of cortical information transactions, where synchronization of beta-gamma oscillations between distant cortical regions is mediated by widespread theta-alpha oscillations. It is the aim of this paper to express this hypothesis quantitatively, in terms of a model that will allow testing this type of information transaction mechanism. The basic methodology used here corresponds to statistical mediation analysis, originally developed by (Baron and Kenny 1986). We generalize the classical mediator model to the case of multivariate complex-valued data, consisting of the discrete Fourier transform coefficients of signals of electric neuronal activity, at different frequencies, and at different cortical locations. The "mediation effect" is quantified here in a novel way, as the product of "dual frequency RV-coupling coefficients", that were introduced in (Pascual-Marqui et al 2016, http://arxiv.org/abs/1603.05343). Relevant statistical procedures are presented for testing the cross-frequency mediation mechanism in general, and in particular for testing the von Stein & Sarnthein hypothesis.Comment: https://doi.org/10.1101/119362 licensed as CC-BY-NC-ND 4.0 International license: http://creativecommons.org/licenses/by-nc-nd/4.0

The dual frequency RV-coupling coefficient: a novel measure for quantifying cross-frequency information transactions in the brain

Identifying dynamic transactions between brain regions has become increasingly important. Measurements within and across brain structures, demonstrating the occurrence of bursts of beta/gamma oscillations only during one specific phase of each theta/alpha cycle, have motivated the need to advance beyond linear and stationary time series models. Here we offer a novel measure, namely, the "dual frequency RV-coupling coefficient", for assessing different types of frequency-frequency interactions that subserve information flow in the brain. This is a measure of coherence between two complex-valued vectors, consisting of the set of Fourier coefficients for two different frequency bands, within or across two brain regions. RV-coupling is expressed in terms of instantaneous and lagged components. Furthermore, by using normalized Fourier coefficients (unit modulus), phase-type couplings can also be measured. The dual frequency RV-coupling coefficient is based on previous work: the second order bispectrum, i.e. the dual-frequency coherence (Thomson 1982; Haykin & Thomson 1998); the RV-coefficient (Escoufier 1973); Gorrostieta et al (2012); and Pascual-Marqui et al (2011). This paper presents the new measure, and outlines relevant statistical tests. The novel aspects of the "dual frequency RV-coupling coefficient" are: (1) it can be applied to two multivariate time series; (2) the method is not limited to single discrete frequencies, and in addition, the frequency bands are treated by means of appropriate multivariate statistical methodology; (3) the method makes use of a novel generalization of the RV-coefficient for complex-valued multivariate data; (4) real and imaginary covariance contributions to the RV-coherence are obtained, allowing the definition of a "lagged-coupling" measure that is minimally affected by the low spatial resolution of estimated cortical electric neuronal activity.Comment: technical report, pre-print, 2016-03-1

High throughput imaging cytometer with acoustic focussing

We demonstrate an imaging flow cytometer that uses acoustic levitation to assemble cells and other particles into a sheet structure. This technique enables a high resolution, low noise CMOS camera to capture images of thousands of cells with each frame. While ultrasonic focussing has previously been demonstrated for 1D cytometry systems, extending the technology to a planar, much higher throughput format and integrating imaging is non-trivial, and represents a significant jump forward in capability, leading to diagnostic possibilities not achievable with current systems. A galvo mirror is used to track the images of the moving cells permitting exposure times of 10 ms at frame rates of 50 fps with motion blur of only a few pixels. At 80 fps, we demonstrate a throughput of 208 000 beads per second. We investigate the factors affecting motion blur and throughput, and demonstrate the system with fluorescent beads, leukaemia cells and a chondrocyte cell line. Cells require more time to reach the acoustic focus than beads, resulting in lower throughputs; however a longer device would remove this constraint

Inhibitory Effects of Anti-VEGF Antibody on the Growth and Angiogenesis of Estrogen-induced Pituitary Prolactinoma in Fischer 344 Rats: Animal Model of VEGF-targeted Therapy for Human Endocrine Tumors

Estrogen-induced pituitary prolactin-producing tumors (PRLoma) in F344 rats express a high level of vascular endothelial growth factor (VEGF) associated with marked angiogenesis and angiectasis. To investigate whether tumor development in E2-induced PRLoma is inhibited by anti-VEGF monoclonal antibody (G6-31), we evaluated tumor growth and observed the vascular structures. With simultaneous treatment with G6-31 for the latter three weeks of the 13-week period of E2 stimulation (E2+G6-31 group), the following inhibitory effects on the PRLoma were observed in the E2+G6-31 group as compared with the E2-only group. In the E2+G6-31 group, a tendency to reduction in pituitary weight was observed and significant differences were observed as (1) reductions in the Ki-67-positive anterior cells, (2) increases in TUNEL-positive anterior cells, and (3) repair of the microvessel count by CD34-immunohistochemistry. The characteristic “blood lakes” in PRLomas were improved and replaced by repaired microvascular structures on 3D observation using confocal laser scanning microscope. These inhibitory effects due to anti-VEGF antibody might be related to the autocrine/paracrine action of VEGF on the tumor cells, because VEGF and its receptor are co-expressed on the tumor cells. Thus, our results demonstrate that anti-VEGF antibody exerted inhibitory effects on pituitary tumorigenesis in well-established E2 induced PRLomas

Myelin Basic Protein as a Novel Genetic Risk Factor in Rheumatoid Arthritis—A Genome-Wide Study Combined with Immunological Analyses

Rheumatoid arthritis (RA) is a major cause of adult chronic inflammatory arthritis and a typical complex trait. Although several genetic determinants have been identified, they account for only a part of the genetic susceptibility. We conducted a genome-wide association study of RA in Japanese using 225,079 SNPs genotyped in 990 cases and 1,236 controls from two independent collections (658 cases and 934 controls in collection1; 332 cases and 302 controls in collection2), followed by replication studies in two additional collections (874 cases and 855 controls in collection3; 1,264 cases and 948 controls in collection4). SNPs showing p<0.005 in the first two collections and p<10−4 by meta-analysis were further genotyped in the latter two collections. A novel risk variant, rs2000811, in intron2 of the myelin basic protein (MBP) at chromosome 18q23 showed strong association with RA (p = 2.7×10−8, OR 1.23, 95% CI: 1.14–1.32). The transcription of MBP was significantly elevated with the risk allele compared to the alternative allele (p<0.001). We also established by immunohistochemistry that MBP was expressed in the synovial lining layer of RA patients, the main target of inflammation in the disease. Circulating autoantibody against MBP derived from human brain was quantified by ELISA between patients with RA, other connective tissue diseases and healthy controls. As a result, the titer of anti-MBP antibody was markedly higher in plasma of RA patients compared to healthy controls (p<0.001) and patients with other connective tissue disorders (p<0.001). ELISA experiment using citrullinated recombinant MBP revealed that a large fraction of anti-MBP antibody in RA patients recognized citrullinated MBP. This is the first report of a genetic study in RA implicating MBP as a potential autoantigen and its involvement in pathogenesis of the disease

Caucasian and Asian Specific Rheumatoid Arthritis Risk Loci Reveal Limited Replication and Apparent Allelic Heterogeneity in North Indians

Genome-wide association studies and meta-analysis indicate that several genes/loci are consistently associated with rheumatoid arthritis (RA) in European and Asian populations. To evaluate the transferability status of these findings to an ethnically diverse north Indian population, we performed a replication analysis. We investigated the association of 47 single-nucleotide polymorphisms (SNPs) at 43 of these genes/loci with RA in a north Indian cohort comprising 983 RA cases and 1007 age and gender matched controls. Genotyping was done using Infinium human 660w-quad. Association analysis by chi-square test implemented in plink was carried out in two steps. Firstly, association of the index or surrogate SNP (r2>0.8, calculated from reference GIH Hap-Map population) was tested. In the second step, evidence for allelic/locus heterogeneity at aforementioned genes/loci was assessed for by testing additional flanking SNPs in linkage equilibrium with index/surrogate marker

Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice

<p>Abstract</p> <p>Background</p> <p>Obesity and related metabolic abnormalities, including inflammation and lipid accumulation in the liver, play a role in liver carcinogenesis. Adipocytokine imbalances, such as decreased serum adiponectin levels, are also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of pitavastatin - a drug used for the treatment of hyperlipidemia - on the development of diethylnitrosamine (DEN)-induced liver preneoplastic lesions in C57BL/KsJ-<it>db/db </it>(<it>db/db</it>) obese mice.</p> <p>Methods</p> <p>Male <it>db/db </it>mice were administered tap water containing 40 ppm DEN for 2 weeks and were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 14 weeks.</p> <p>Results</p> <p>At sacrifice, feeding with 10 ppm pitavastatin significantly inhibited the development of hepatic premalignant lesions, foci of cellular alteration, as compared to that in the untreated group by inducing apoptosis, but inhibiting cell proliferation. Pitavastatin improved liver steatosis and activated the AMPK-α protein in the liver. It also decreased free fatty acid and aminotransferases levels, while increasing adiponectin levels in the serum. The serum levels of tumor necrosis factor (TNF)-α and the expression of <it>TNF-α </it>and <it>interleukin-6 </it>mRNAs in the liver were decreased by pitavastatin treatment, suggesting attenuation of the chronic inflammation induced by excess fat deposition.</p> <p>Conclusions</p> <p>Pitavastatin is effective in inhibiting the early phase of obesity-related liver tumorigenesis and, therefore, may be useful in the chemoprevention of liver cancer in obese individuals.</p