Multivoxel Pattern Analysis Reveals Auditory Motion Information in MT+ of Both Congenitally Blind and Sighted Individuals

Cross-modal plasticity refers to the recruitment of cortical regions involved in the processing of one modality (e.g. vision) for processing other modalities (e.g. audition). The principles determining how and where cross-modal plasticity occurs remain poorly understood. Here, we investigate these principles by testing responses to auditory motion in visual motion area MT+ of congenitally blind and sighted individuals. Replicating previous reports, we find that MT+ as a whole shows a strong and selective responses to auditory motion in congenitally blind but not sighted individuals, suggesting that the emergence of this univariate response depends on experience. Importantly, however, multivoxel pattern analyses showed that MT+ contained information about different auditory motion conditions in both blind and sighted individuals. These results were specific to MT+ and not found in early visual cortex. Basic sensitivity to auditory motion in MT+ is thus experience-independent, which may be a basis for the region's strong cross-modal recruitment in congenital blindness

Astroglial excitability and gliotransmission: an appraisal of Ca2+ as a signalling route

Astroglial cells, due to their passive electrical properties, were long considered subservient to neurons and to merely provide the framework and metabolic support of the brain. Although astrocytes do play such structural and housekeeping roles in the brain, these glial cells also contribute to the brain's computational power and behavioural output. These more active functions are endowed by the Ca2+-based excitability displayed by astrocytes. An increase in cytosolic Ca2+ levels in astrocytes can lead to the release of signalling molecules, a process termed gliotransmission, via the process of regulated exocytosis. Dynamic components of astrocytic exocytosis include the vesicular-plasma membrane secretory machinery, as well as the vesicular traffic, which is governed not only by general cytoskeletal elements but also by astrocyte-specific IFs (intermediate filaments). Gliotransmitters released into the ECS (extracellular space) can exert their actions on neighbouring neurons, to modulate synaptic transmission and plasticity, and to affect behaviour by modulating the sleep homoeostat. Besides these novel physiological roles, astrocytic Ca2+ dynamics, Ca2+-dependent gliotransmission and astrocyte–neuron signalling have been also implicated in brain disorders, such as epilepsy. The aim of this review is to highlight the newer findings concerning Ca2+ signalling in astrocytes and exocytotic gliotransmission. For this we report on Ca2+ sources and sinks that are necessary and sufficient for regulating the exocytotic release of gliotransmitters and discuss secretory machinery, secretory vesicles and vesicle mobility regulation. Finally, we consider the exocytotic gliotransmission in the modulation of synaptic transmission and plasticity, as well as the astrocytic contribution to sleep behaviour and epilepsy

On-chip generation of high-dimensional entangled quantum states and their coherent control

Optical quantum states based on entangled photons are essential for solving questions in fundamental physics and are at the heart of quantum information science1. Specifically, the realization of high-dimensional states (D-level quantum systems, that is, qudits, with D > 2) and their control are necessary for fundamental investigations of quantum mechanics2, for increasing the sensitivity of quantum imaging schemes3, for improving the robustness and key rate of quantum communication protocols4, for enabling a richer variety of quantum simulations5, and for achieving more efficient and error-tolerant quantum computation6. Integrated photonics has recently become a leading platform for the compact, cost-efficient, and stable generation and processing of non-classical optical states7. However, so far, integrated entangled quantum sources have been limited to qubits (D = 2)8, 9, 10, 11. Here we demonstrate on-chip generation of entangled qudit states, where the photons are created in a coherent superposition of multiple high-purity frequency modes. In particular, we confirm the realization of a quantum system with at least one hundred dimensions, formed by two entangled qudits with D = 10. Furthermore, using state-of-the-art, yet off-the-shelf telecommunications components, we introduce a coherent manipulation platform with which to control frequency-entangled states, capable of performing deterministic high-dimensional gate operations. We validate this platform by measuring Bell inequality violations and performing quantum state tomography. Our work enables the generation and processing of high-dimensional quantum states in a single spatial mode

Dopamine Signaling Is Essential for Precise Rates of Locomotion by C. elegans

Dopamine is an important neuromodulator in both vertebrates and invertebrates. We have found that reduced dopamine signaling can cause a distinct abnormality in the behavior of the nematode C. elegans, which has only eight dopaminergic neurons. Using an automated particle-tracking system for the analysis of C. elegans locomotion, we observed that individual wild-type animals made small adjustments to their speed to maintain constant rates of locomotion. By contrast, individual mutant animals defective in the synthesis of dopamine made larger adjustments to their speeds, resulting in large fluctuations in their rates of locomotion. Mutants defective in dopamine signaling also frequently exhibited both abnormally high and abnormally low average speeds. The ability to make small adjustments to speed was restored to these mutants by treatment with dopamine. These behaviors depended on the D2-like dopamine receptor DOP-3 and the G-protein subunit GOA-1. We suggest that C. elegans and other animals, including humans, might share mechanisms by which dopamine restricts motor activity levels and coordinates movement

Physicochemical and biological characterization of 1E10 Anti-Idiotype vaccine

<p>Abstract</p> <p>Background</p> <p>1E10 monoclonal antibody is a murine anti-idiotypic antibody that mimics N-glycolyl-GM3 gangliosides. This antibody has been tested as an anti-idiotypic cancer vaccine, adjuvated in Al(OH)₃, in several clinical trials for melanoma, breast, and lung cancer. During early clinical development this mAb was obtained <it>in vivo </it>from mice ascites fluid. Currently, the production process of 1E10 is being transferred from the <it>in vivo </it>to a bioreactor-based method.</p> <p>Results</p> <p>Here, we present a comprehensive molecular and immunological characterization of 1E10 produced by the two different production processes in order to determine the impact of the manufacturing process in vaccine performance. We observed differences in glycosylation pattern, charge heterogeneity and structural stability between <it>in vivo</it>-produced 1E10 and bioreactor-obtained 1E10. Interestingly, these modifications had no significant impact on the immune responses elicited in two different animal models.</p> <p>Conclusions</p> <p>Changes in 1E10 primary structure like glycosylation; asparagine deamidation and oxidation affected 1E10 structural stability but did not affect the immune response elicited in mice and chickens when compared to 1E10 produced in mice.</p

Overexposure to apoptosis via disrupted glial specification perturbs Drosophila macrophage function and reveals roles of the CNS during injury

Apoptotic cell clearance by phagocytes is a fundamental process during development, homeostasis and the resolution of inflammation. However, the demands placed on phagocytic cells such as macrophages by this process, and the limitations these interactions impose on subsequent cellular behaviours are not yet clear. Here, we seek to understand how apoptotic cells affect macrophage function in the context of a genetically tractable Drosophila model in which macrophages encounter excessive amounts of apoptotic cells. Loss of the glial-specific transcription factor Repo prevents glia from contributing to apoptotic cell clearance in the developing embryo. We show that this leads to the challenge of macrophages with large numbers of apoptotic cells in vivo. As a consequence, macrophages become highly vacuolated with cleared apoptotic cells, and their developmental dispersal and migration is perturbed. We also show that the requirement to deal with excess apoptosis caused by a loss of repo function leads to impaired inflammatory responses to injury. However, in contrast to migratory phenotypes, defects in wound responses cannot be rescued by preventing apoptosis from occurring within a repo mutant background. In investigating the underlying cause of these impaired inflammatory responses, we demonstrate that wound-induced calcium waves propagate into surrounding tissues, including neurons and glia of the ventral nerve cord, which exhibit striking calcium waves on wounding, revealing a previously unanticipated contribution of these cells during responses to injury. Taken together, these results demonstrate important insights into macrophage biology and how repo mutants can be used to study macrophage–apoptotic cell interactions in the fly embryo. Furthermore, this work shows how these multipurpose cells can be ‘overtasked’ to the detriment of their other functions, alongside providing new insights into which cells govern macrophage responses to injury in vivo

The PDZ Protein Canoe/AF-6 Links Ras-MAPK, Notch and Wingless/Wnt Signaling Pathways by Directly Interacting with Ras, Notch and Dishevelled

Over the past few years, it has become increasingly apparent that signal transduction pathways are not merely linear cascades; they are organized into complex signaling networks that require high levels of regulation to generate precise and unique cell responses. However, the underlying regulatory mechanisms by which signaling pathways cross-communicate remain poorly understood. Here we show that the Ras-binding protein Canoe (Cno)/AF-6, a PDZ protein normally associated with cellular junctions, is a key modulator of Wingless (Wg)/Wnt, Ras-Mitogen Activated Protein Kinase (MAPK) and Notch (N) signaling pathways cross-communication. Our data show a repressive effect of Cno/AF-6 on these three signaling pathways through physical interactions with Ras, N and the cytoplasmic protein Dishevelled (Dsh), a key Wg effector. We propose a model in which Cno, through those interactions, actively coordinates, at the membrane level, Ras-MAPK, N and Wg signaling pathways during progenitor specification

A regulated deficit irrigation strategy for hedgerow olive orchards with high plant density

Background & Aims There is not a consensus on the best irrigation approach for super-high density (SHD) olive orchards. Our aim was to design and test a regulated deficit irrigation (RDI) strategy for a sustainable balance between water saving, tree vigour and oil production. Methods We tested our RDI strategy for 3 years in an ‘Arbequina’ orchard with 1,667 trees ha−1. Two levels of irrigation reduction were applied, 60RDI and 30RDI, scaled to replacing 60 % and 30 %, respectively, of the of irrigation needs (IN). We also had a full irrigation (FI) treatment as control, with IN totalling 4,701 m3 ha−1 Results The 30RDI treatment showed the best balance between water saving, tree vigour and oil production. With a yearly irrigation amount (IA) of 1,366 m3 ha−1, which meant 72 % water saving as compared to FI, the reduction in oil yield was 26 % only. Conclusions Our results, together with recent knowledge on the effect of water stress on fruit development, allowed us to suggest a potentially improved RDI strategy for which a total IA of ca. 2,100 m3 ha−1 was calculated. Both some management details and the benefits of this suggested RDI strategy are still to be tested

A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer

BACKGROUND: Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy. METHODOLOGY: This was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day –7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate. MAIN FINDINGS: 16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1–2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5(m)C content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively. CONCLUSIONS: Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy

Regulated Fluctuations in Nanog Expression Mediate Cell Fate Decisions in Embryonic Stem Cells

The notion that the differentiated state of a cell population is determined simply by expression of specific marker genes is changing. In this work, the authors reveal that a pluripotent cell population comprises cells with temporal fluctuations in the expression of Nanog