Visual feature-tolerance in the reading network

A century of neurology and neuroscience shows that seeing words depends on ventral occipital-temporal (VOT) circuitry. Typically, reading is learned using high-contrast line-contour words. We explored whether a specific VOT region, the visual word form area (VWFA), learns to see only these words or recognizes words independent of the specific shape-defining visual features. Word forms were created using atypical features (motion-dots, luminance-dots) whose statistical properties control word-visibility. We measured fMRI responses as word form visibility varied, and we used TMS to interfere with neural processing in specific cortical circuits, while subjects performed a lexical decision task. For all features, VWFA responses increased with word-visibility and correlated with performance. TMS applied to motion-specialized area hMT+ disrupted reading performance for motion-dots, but not line-contours or luminance-dots. A quantitative model describes feature-convergence in the VWFA and relates VWFA responses to behavioral performance. These findings suggest how visual feature-tolerance in the reading network arises through signal convergence from feature-specialized cortical areas.     

The In Vivo Therapeutic Efficacy of the Oncolytic Adenovirus Delta24-RGD Is Mediated by Tumor-Specific Immunity

The oncolytic adenovirus Delta24-RGD represents a new promising therapeutic agent for patients with a malignant glioma and is currently under investigation in clinical phase I/II trials. Earlier preclinical studies showed that Delta24-RGD is able to effectively lyse tumor cells, yielding promising results in various immune-deficient glioma models. However, the role of the immune response in oncolytic adenovirus therapy for glioma has never been explored. To this end, we assessed Delta24-RGD treatment in an immune-competent orthotopic mouse model for glioma and evaluated immune responses against tumor and virus. Delta24-RGD treatment led to long-term survival in 50% of mice and this effect was completely lost upon administration of the immunosuppressive agent dexamethasone. Delta24-RGD enhanced intra-tumoral infiltration of F4/80+ macrophages, CD4+ and CD8+ T-cells, and increased the local production of pro-inflammatory cytokines and chemokines. In treated mice, T cell responses were directed to the virus as well as to the tumor cells, which was reflected in the presence of protective immunological memory in mice that underwent tumor rechallenge. Together, these data provide evidence that the immune system plays a vital role in the therapeutic efficacy of oncolytic adenovirus therapy of glioma, and may provide angles to future improvements on Delta24-RGD therapy.     

Human TCR that incorporate CD3zeta induce highly preferred pairing between TCRalpha and beta chains following gene transfer

TCR gene therapy is adversely affected by newly formed TCRalphabeta heterodimers comprising exogenous and endogenous TCR chains that dilute expression of transgenic TCRalphabeta dimers and are potentially self-reactive. We have addressed TCR mispairing by using a modified two-chain TCR that encompasses total human CD3zeta with specificities for three different Ags. Transfer of either TCRalpha:CD3zeta or beta:CD3zeta genes alone does not result in surface expression, whereas transfer of both modified TCR chains results in high surface expression, binding of peptide-MHC complexes and Ag-specific T cell functions. Genetic introduction of TCRalphabeta:zeta does not compromise surface expression and functions of an endogenous TCRalphabeta. Flow cytometry fluorescence resonance energy transfer and biochemical analyses demonstrate that TCRalphabeta:CD3zeta is the first strategy that results in highly preferred pairing between CD3zeta-modified TCRalpha and beta chains as well as absence of TCR mispairing between TCR:CD3zeta and nonmodified TCR chains. Intracellular assembly and surface expression of TCR:CD3zeta chains is independent of endogenous CD3gamma, delta, and epsilon. Taken together, our data support the use of TCRalphabeta:CD3zeta to prevent TCR mispairing, which may provide an adequate strategy to enhance efficacy and safety of TCR gene transfer.     

Anatomy of flower and fruit of <i>Vassobia breviflora</i> (Solanaceae) in the south of the southern Yungas (Argentina)

Solanaceae is a family with nearly 2400 species of cosmopolitan distribution. Vassobia breviflora is the only species of the genus present in Argentina. The goal of this work was to review and characterize the anatomy of the flower and fruit of V. breviflora from samples collected in populations of Yungas in the argentine Northwest. Conventional anatomical techniques were applied. The results showed that most flower, fruit and seed structures did not differ from those previously reported regarding the structural organization described for other species of the Solanaceae family. However, for the first time, we described the androecium, fruit, seed, floral and fruit pedicels, five types of tricomes and five types of stomata in the perianth. We found some differences in the shape of the transmission tissue and in the type of ovule with respect to that previously reported. Also, we located the parenchyma and the epidermic secretory cells of the nectary. In the context of the family Solanaceae, we discussed the function and diagnostic value of the described structures.     

Growth plate formation and development in alligator and mouse metapodials: evolutionary and functional implications

Mammalian metapodials (metacarpals and metatarsals), unlike most long bones, form a single growth plate, and undergo longitudinal growth at only one end. The growth dynamics of non-mammalian tetrapod metapodials have not been systematically examined in order to determine if unidirectional growth is unique to mammals. Here we compare murine metapodial ossification in growth stages that parallel those of embryonic, juvenile and subadult American alligators (Alligator mississippiensis). Safranin O staining was used for qualitative histology, and chondrocyte differentiation and proliferation were assessed via immunohistochemistry for type X collagen and proliferative cell nuclear antigen (PCNA). We establish that growth plates form at both ends of alligator metapodials and are maintained in the subadult. PCNA results show that alligators and mice share common patterns of chondrocyte proliferation during growth plate formation. In addition, while alligators and mice differ initially in the degree of organization and pace of chondrocyte differentiation, these parameters are largely similar in established growth plates. However, the replacement of cartilage by bone is highly irregular throughout growth in the alligator, in contrast to the more uniform process in the mouse. These results indicate that while alligators and mammals share common mechanisms of chondrocyte regulation, they differ substantially in their processes of ossification. Phylogenetic analysis indicates that the direct ossification of one epiphysis and reliance on a single growth plate is a derived character (synapomorphy) in therian mammals and likely indicates an adaptation for erect quadrupedal gait.     

Neuropeptides regulate expression of matrix molecule, growth factor and inflammatory mediator mRNA in explants of normal and healing medial collateral ligament

Denervation degrades normal ligament properties and impairs ligament healing. This suggests that secreted neuromediators, such as neuropeptides, could be modulating cell metabolism in ligament and scar tissue. To test this hypothesis we investigated the effect of exogenous substance P (SP), neuropeptide Y (NPY) or calcitonin gene-related peptide (CGRP) on the mRNA levels for proteins associated with inflammation, angiogenesis, and matrix production in tissue-cultured specimens of normal and injured medial collateral ligament. SP and NPY induced increased mRNA levels for several inflammatory mediators in the 2-week post-injury specimens. All three neuropeptides induced decreases in mRNA levels for healing-associated growth factors and matrix molecules, including basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and collagen types I and III. The results indicate that neuropeptides strongly influence the metabolic activity of cells in healing ligament, particularly at early time points after injury.     

Combination of IL-21 and IL-15 enhances tumour-specific cytotoxicity and cytokine production of TCR-transduced primary T cells

IL-21, and to a lesser extent IL-15, inhibits differentiation of antigen-primed CD8 T cells and promotes their homeostasis and anti-tumour activity. Here, we investigated molecular mechanisms behind tumour-specific responses of primary murine T lymphocytes engineered to express a TCR directed against human gp100/HLA-A2 following short-term exposure to IL-15 and/or IL-21. We demonstrated that IL-15 + IL-21, and to a lesser extent IL-21, enhanced antigen-specific T-cell cytotoxicity, which was related to enhanced expression of granzymes A and B, and perforin 1. Furthermore, IL-15 + IL-21 synergistically enhanced release levels and kinetics of T-cell IFNγ and IL-2, but not IL-10. Enhanced secretion of IFNγ was accompanied by increased gene expression and cytosolic protein content, and was restricted to effector memory T cells. To summarize, we show that IL-15 + IL-21 improves antigen-specific responses of TCR-transduced effector T cells at multiple levels, which provides a rationale to treat T cells with a combination of these cytokines prior to their use in adoptive TCR gene therapy.     

An enlarged postcranial sample confirms Australopithecus afarensis dimorphism was similar to modern humans

In a previous study, we introduced the template method as a means of enlarging the Australopithecus afarensis postcranial sample to more accurately estimate its skeletal dimorphism. Results indicated dimorphism to be largely comparable to that of Homo sapiens. Some have since argued that our results were biased by artificial homogeneity in our Au. afarensis sample. Here we report the results from inclusion of 12 additional, newly reported, specimens. The results are consistent with those of our original study and with the hypothesis that early hominid demographic success derived from a reproductive strategy involving male provisioning of pair-bonded females.