Combining Transcranial Magnetic Stimulation and fMRI to Examine the Default Mode Network

The default mode network is a group of brain regions that are active when an individual is not focused on the outside world and the brain is at "wakeful rest."^1,2,3 It is thought the default mode network corresponds to self-referential or "internal mentation".^2,3It has been hypothesized that, in humans, activity within the default mode network is correlated with certain pathologies (for instance, hyper-activation has been linked to schizophrenia ^4,5,6 and autism spectrum disorders ⁷ whilst hypo-activation of the network has been linked to Alzheimer''s and other neurodegenerative diseases ⁸). As such, noninvasive modulation of this network may represent a potential therapeutic intervention for a number of neurological and psychiatric pathologies linked to abnormal network activation. One possible tool to effect this modulation is Transcranial Magnetic Stimulation: a non-invasive neurostimulatory and neuromodulatory technique that can transiently or lastingly modulate cortical excitability (either increasing or decreasing it) via the application of localized magnetic field pulses.⁹In order to explore the default mode network''s propensity towards and tolerance of modulation, we will be combining TMS (to the left inferior parietal lobe) with functional magnetic resonance imaging (fMRI). Through this article, we will examine the protocol and considerations necessary to successfully combine these two neuroscientific tools.Download video file.^{(68M, mov)}     

The molecular biology and immunology of glioblastoma multiforme (GBM) with the presentation of an immunotherapy protocol for a clinical trial

After a short explanatory Introduction, an immunotherapy protocol is presented for glioblastoma multiforme (GBM). GBM is considered to be an incurable tumor; tumor-free survival over 2 to 3 years is so rare that when it happens the original diagnosis is questioned. It is known that the type of the genetic mutation that a given GBM tumor harbors strongly influences the length of survival. However, most patients with GBM are receiving treatment without the preparation of a microarray gene map of their tumors. It is possible that the reason for a rare and exceptional long survival was not the treatment that the patient received, but the type of gene mutations that the tumor was exposed to. It is recognized that any therapeutic approach should ideally be evaluated against the background of all prognostic factors of each individual case, prominent among them the microarray gene map of the tumor. In practice, this is not easily achieved, while the patient is in need of, and is expecting, prompt therapy. Insurance companies do not reimburse the patient, or the clinical investigators, or their institutions for investigational diagnostic tests, or such treatment modalities. A temporary compromise is possible. The emergence of empirically administered treatment modalities with extraordinary efficacy has occasionally been recorded in the history of medical oncology. In some of these rare clinical trials, the control groups were discontinued (to the dismay of the statisticians), and the control patients were enrolled in the treatment groups so to escape doom and share the benefit of the unfolding high remission inductions experienced in the treatment group. Chemo-radiotherapy of Hodgkin's disease and cisplatin therapy of certain testicular carcinomas provided the first éclat examples. More recently, the rapidly approved and marketed imitanib mesylate for Ph-chromosome-positive chronic myelogenous leukemia and the anti-HER2/neu monoclonal antibody trastuzumab, and the not yet marketed double tyrosine kinase (ErbB1/2) inhibitor lapatinib (Tykerb, GlaxoSmithKline) for a subgroup of breast carcinoma patients excelled. Thus, a clinical trial for GBM, but without precise pre-identification of all its prognostic factors, however with a great deal of evidence-based empirical expectations of benefits, for patients with rapid advarcement toward a fatal outcome, implying an element of urgency, appears to be justified.     

Biological activity of paramyxovirus fusion proteins: factors influencing formation of syncytia.

The fusion (F) and hemagglutinin-neuraminidase (HN) glycoproteins of the paramyxovirus simian virus 5 (SV5) were expressed individually or coexpressed in CV-1 cells by using SV40-based vectors and recombinant vaccinia viruses. The extent of detectable fusion in a syncytium formation assay was found to be affected by the expression system used. In addition, when HN was coexpressed with F, it was found that the expression vector system influenced the contribution of HN in forming syncytia. The abilities of the SV5, human parainfluenza virus type 3, and Newcastle disease virus F glycoproteins to cause fusion, when expressed alone or coexpressed with HN, were directly compared by using the SV40-based vector system in CV-1 cells. The F proteins exhibited various degrees of fusion activity independent of HN expression, but the formation of syncytia could be enhanced to different extents by the coexpression of the homotypic HN protein.     

Using a pericentromeric interspersed repeat to recapitulate the phylogeny and expansion of human centromeric segmental duplications

Despite considerable advances in sequencing of the human genome over the past few years, the organization and evolution of human pericentromeric regions have been difficult to resolve. This is due, in part, to the presence of large, complex blocks of duplicated genomic sequence at the boundary between centromeric satellite and unique euchromatic DNA. Here, we report the identification and characterization of an approximately 49-kb repeat sequence that exists in more than 40 copies within the human genome. This repeat is specific to highly duplicated pericentromeric regions with multiple copies distributed in an interspersed fashion among a subset of human chromosomes. Using this interspersed repeat (termed PIR4) as a marker of pericentromeric DNA, we recovered and sequence-tagged 3 Mb of pericentromeric DNA from a variety of human chromosomes as well as nonhuman primate genomes. A global evolutionary reconstruction of the dispersal of PIR4 sequence and analysis of flanking sequence supports a model in which pericentromeric duplications initiated before the separation of the great ape species (>12 MYA). Further, analyses of this duplication and associated flanking duplications narrow the major burst of pericentromeric duplication activity to a time just before the divergence of the African great ape and human species (5 to 7 MYA). These recent duplication exchange events substantially restructured the pericentromeric regions of hominoid chromosomes and created an architecture where large blocks of sequence are shared among nonhomologous chromosomes. This report provides the first global view of the series of historical events that have reshaped human pericentromeric regions over recent evolutionary time.     

Arabidopsis microarrays identify conserved and differentially expressed genes involved in shoot growth and development from distantly related plant species

Expressed sequence tags (EST)-based microarrays are powerful tools for gene discovery and signal transduction studies in a small number of well-characterized species. To explore the usefulness of this technique for poorly characterized species, we have hybridized the 11,522-element Arabidopsis microarrays with labeled cDNAs from mature leaf and shoot apices from several different species. Expression of 23 to 47% of the genes on the array was detected, demonstrating that a large number of genes from distantly related species can be surveyed on Arabidopsis arrays. Differential expression of genes with known functions was indicative of the physiological state of the tissues tested. Genes involved in cell division, stress responses, and development were conserved and expressed preferentially in growing shoots.