Modular Acquisition and Stimulation System for Timestamp-Driven Neuroscience Experiments

Dedicated systems are fundamental for neuroscience experimental protocols that require timing determinism and synchronous stimuli generation. We developed a data acquisition and stimuli generator system for neuroscience research, optimized for recording timestamps from up to 6 spiking neurons and entirely specified in a high-level Hardware Description Language (HDL). Despite the logic complexity penalty of synthesizing from such a language, it was possible to implement our design in a low-cost small reconfigurable device. Under a modular framework, we explored two different memory arbitration schemes for our system, evaluating both their logic element usage and resilience to input activity bursts. One of them was designed with a decoupled and latency insensitive approach, allowing for easier code reuse, while the other adopted a centralized scheme, constructed specifically for our application. The usage of a high-level HDL allowed straightforward and stepwise code modifications to transform one architecture into the other. The achieved modularity is very useful for rapidly prototyping novel electronic instrumentation systems tailored to scientific research.Comment: Preprint submitted to ARC 2015. Extended: 16 pages, 10 figures. The final publication is available at link.springer.co

Variations of Steroid Hormone Metabolites in Serum and Urine in Polycystic Ovary Syndrome after Nafarelin Stimulation: Evidence for an Altered Corticoid Excretion.

To evaluate the clinical relevance of testing pituitary-ovarian responses in patients suffering from polycystic ovary syndrome (PCOS) with the GnRH agonist nafarelin, a 1.2-mg dose of nafarelin was given intranasally to 19 women with PCOS and 15 healthy premenopausal women. The subsequent analysis of steroids in both serum and urine during the test was carried out at several time points for up to 24 h. Serum levels of 17 alpha-hydroxyprogesterone were elevated at all time points of the test in PCOS patients vs. controls [at baseline, 3.5 +/- 0.2 vs. 1.8 +/- 0.1 nmol/L (P < 0.001); at 24 h, 9.9 +/- 0.9 vs. 4.9 +/- 0.3 nmol/L (P < 0.001)]. Basal levels of androstenedione were higher in the patient group, but there was no significant change during the test in either group. Serum testosterone levels were also found to differ in PCOS patients compared with the control values at baseline (2.2 +/- 0.2 vs. 1.5 +/- 0.1 nmol/L; P < 0.05) and after nafarelin treatment (at 24 h, 3.2 +/- 0.4 vs. 1.8 +/- 0.2 nmol/L; P < 0.05). Serum estradiol levels rose significantly in both groups during the test; the posttest levels were significantly higher in PCOS than in controls. The PCOS patients displayed a significant increase in androgen and gestagen metabolites as well as in glucocorticoid metabolites excreted in the urine during the 24 h. In the control subjects, except for 17 alpha-hydroxypregnanolone, which rose significantly, none of the urinary steroids investigated showed relevant changes during the nafarelin test. The posttest excretion of allo-tetrahydrocortisol (1.4 +/- 0.2 vs. 0.3 +/- 0.1 mumol/g creatinine; P < 0.001) and the increase in 17 alpha-hydroxypregnanolone excretion (1.4 +/- 0.2 vs. 0.3 +/- 0.1 mumol/g creatinine; P < 0.001) were distinctly higher in PCOS patients than in the controls; the diagnostic sensitivity of the combination of both parameters was 89% at a 93% specificity. Thus, measurements of 17 alpha-hydroxyprogesterone levels in serum and of urinary allo-tetrahydrocortisol and 17 alpha-hydroxypregnanolone after nafarelin treatment make this stimulation test a valuable diagnostic tool for identifying PCOS patients. The significant changes in the excretion of urinary androgen and gestagen metabolites, unmasked by GnRH agonist stimulation, suggest a functional alteration of the pituitary-ovarian axis. The reason for the increased excretion of glucocorticoid metabolites after nafarelin stimulation remains to be clarified

Folding of the Triangular Lattice with Quenched Random Bending Rigidity

We study the problem of folding of the regular triangular lattice in the presence of a quenched random bending rigidity + or - K and a magnetic field h (conjugate to the local normal vectors to the triangles). The randomness in the bending energy can be understood as arising from a prior marking of the lattice with quenched creases on which folds are favored. We consider three types of quenched randomness: (1) a ``physical'' randomness where the creases arise from some prior random folding; (2) a Mattis-like randomness where creases are domain walls of some quenched spin system; (3) an Edwards-Anderson-like randomness where the bending energy is + or - K at random independently on each bond. The corresponding (K,h) phase diagrams are determined in the hexagon approximation of the cluster variation method. Depending on the type of randomness, the system shows essentially different behaviors.Comment: uses harvmac (l), epsf, 17 figs included, uuencoded, tar compresse

Testing the theory of immune selection in cancers that break the rules of transplantation

Modification of cancer cells likely to reduce their immunogenicity, including loss or down-regulation of MHC molecules, is now well documented and has become the main support for the concept of immune surveillance. The evidence that these modifications, in fact, result from selection by the immune system is less clear, since the possibility that they may result from reorganized metabolism associated with proliferation or from cell de-differentiation remains. Here, we (a) survey old and new transplantation experiments that test the possibility of selection and (b) survey how transmissible tumours of dogs and Tasmanian devils provide naturally evolved tests of immune surveillance

Real-world clinical experience with Idebenone in the treatment of Leber hereditary optic neuropathy

Background: Leber hereditary optic neuropathy (LHON) leads to bilateral central vision loss. In a clinical trial setting, idebenone has been shown to be safe and to provide a trend toward improved visual acuity, but long-term evidence of effectiveness in real-world clinical practice is sparse. Methods: Open-label, multicenter, retrospective, noncontrolled analysis of long-term visual acuity and safety in 111 LHON patients treated with idebenone (900 mg/day) in an expanded access program. Eligible patients had a confirmed mitochondrial DNA mutation and had experienced the onset of symptoms (most recent eye) within 1 year before enrollment. Data on visual acuity and adverse events were collected as per normal clinical practice. Efficacy was assessed as the proportion of patients with either a clinically relevant recovery (CRR) or a clinically relevant stabilization (CRS) of visual acuity. In the case of CRR, time to and magnitude of recovery over the course of time were also assessed. Results: At time of analysis, 87 patients had provided longitudinal efficacy data. Average treatment duration was 25.6 months. CRR was observed in 46.0% of patients. Analysis of treatment effect by duration showed that the proportion of patients with recovery and the magnitude of recovery increased with treatment duration. Average gain in best-corrected visual acuity for responders was 0.72 logarithm of the minimal angle of resolution (logMAR), equivalent to more than 7 lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Furthermore, 50% of patients who had a visual acuity below 1.0 logMAR in at least one eye at initiation of treatment successfully maintained their vision below this threshold by last observation. Idebenone was well tolerated, with most adverse events classified as minor. Conclusions: These data demonstrate the benefit of idebenone treatment in recovering lost vision and maintaining good residual vision in a real-world setting. Together, these findings indicate that idebenone treatment should be initiated early and be maintained more than 24 months to maximize efficacy. Safety results were consistent with the known safety profile of idebenone

Interferon-γ Regulates the Proliferation and Differentiation of Mesenchymal Stem Cells via Activation of Indoleamine 2,3 Dioxygenase (IDO)

The kynurenine pathway (KP) of tryptophan metabolism is linked to antimicrobial activity and modulation of immune responses but its role in stem cell biology is unknown. We show that human and mouse mesenchymal and neural stem cells (MSCs and NSCs) express the complete KP, including indoleamine 2,3 dioxygenase 1 (IDO) and IDO2, that it is highly regulated by type I (IFN-β) and II interferons (IFN-γ), and that its transcriptional modulation depends on the type of interferon, cell type and species. IFN-γ inhibited proliferation and altered human and mouse MSC neural, adipocytic and osteocytic differentiation via the activation of IDO. A functional KP present in MSCs, NSCs and perhaps other stem cell types offers novel therapeutic opportunities for optimisation of stem cell proliferation and differentiation

The Immune System Strikes Back: Cellular Immune Responses against Indoleamine 2,3-dioxygenase

The enzyme indoleamine 2,3-dioxygenase (IDO) exerts an well established immunosuppressive function in cancer. IDO is expressed within the tumor itself as well as in antigen-presenting cells in tumor-draining lymph nodes, where it promotes the establishment of peripheral immune tolerance to tumor antigens. In the present study, we tested the notion whether IDO itself may be subject to immune responses.The presence of naturally occurring IDO-specific CD8 T cells in cancer patients was determined by MHC/peptide stainings as well as ELISPOT. Antigen specific cytotoxic T lymphocytes (CTL) from the peripheral blood of cancer patients were cloned and expanded. The functional capacity of the established CTL clones was examined by chrome release assays. The study unveiled spontaneous cytotoxic T-cell reactivity against IDO in peripheral blood as well as in the tumor microenvironment of different cancer patients. We demonstrate that these IDO reactive T cells are indeed peptide specific, cytotoxic effector cells. Hence, IDO reactive T cells are able to recognize and kill tumor cells including directly isolated AML blasts as well as IDO-expressing dendritic cells, i.e. one of the major immune suppressive cell populations.IDO may serve as an important and widely applicable target for anti-cancer immunotherapeutic strategies. Furthermore, as emerging evidence suggests that IDO constitutes a significant counter-regulatory mechanism induced by pro-inflammatory signals, IDO-based immunotherapy holds the promise to boost anti-cancer immunotherapy in general

Group Singing as a Resource for the Development of a Healthy Public

A growing body of evidence points to a wide range of benefits arising from participation in group singing. Group singing requires participants to engage with each other in a simultaneous musical dialogue in a pluralistic and emergent context, creating a coherent cultural expression through the reflexive negotiation of (musical) meaning manifest in the collective power of the human voice. As such, group singing might be taken – both literally and figuratively – as a potent form of ‘healthy public’, creating an ‘ideal’ community which participants can subsequently mobilise as a positive resource for everyday life. The experiences of a group of singers (n=78) who had participated in an outdoor singing project were collected and analysed using a three-layer research design consisting of: distributed data generation and interpretation, considered against comparative data from other singing groups (n=88); a focus group workshop (n=11); an unstructured interview (n=2). The study confirmed an expected perception of the social bonding effect of group singing, highlighting affordances for interpersonal attunement and attachment alongside a powerful individual sense of feeling ‘uplifted’. This study presents a novel perspective on group singing, highlighting the importance of participant experience as a means of understanding music as a holistic and complex adaptive system. It validates findings about group singing from previous studies - in particular the stability of the social bonding effect as a less variant characteristic in the face of environmental and other situational influences, alongside its capacity for mental health recovery. It establishes a subjective sociocultural and musical understanding of group singing, by expanding on these findings to centralise the importance of individual experience, and the consciousness of that experience as descriptive self-awareness. The ways in which participants describe and discuss their experiences of group singing and its benefits points to a complex interdependence between a number of musical, neurobiological and psychosocial mechanisms which might be independently and objectively analysed. An emerging theory is that at least some of the potency of group singing is as a resource where people can rehearse and perform ‘healthy’ relationships, further emphasising its potential as a resource for healthy publics

Psychological Stress-Induced, IDO1-Dependent Tryptophan Catabolism: Implications on Immunosuppression in Mice and Humans

It is increasingly recognized that psychological stress influences inflammatory responses and mood. Here, we investigated whether psychological stress (combined acoustic and restraint stress) activates the tryptophan (Trp) catabolizing enzyme indoleamine 2,3-dioxygenase 1(IDO1) and thereby alters the immune homeostasis and behavior in mice. We measured IDO1 mRNA expression and plasma levels of Trp catabolites after a single 2-h stress session and in repeatedly stressed (4.5-days stress, 2-h twice a day) naïve BALB/c mice. A role of cytokines in acute stress-induced IDO1 activation was studied after IFNγ and TNFα blockade and in IDO1−/− mice. RU486 and 1-Methyl-L-tryptophan (1-MT) were used to study role of glucocorticoids and IDO1 on Trp depletion in altering the immune and behavioral response in repeatedly stressed animals. Clinical relevance was addressed by analyzing IDO1 activity in patients expecting abdominal surgery. Acute stress increased the IDO1 mRNA expression in brain, lung, spleen and Peyer's patches (max. 14.1±4.9-fold in brain 6-h after stress) and resulted in a transient depletion of Trp (−25.2±6.6%) and serotonin (−27.3±4.6%) from the plasma measured 6-h after stress while kynurenine levels increased 6-h later (11.2±9.3%). IDO1 mRNA up-regulation was blocked by anti-TNFα and anti-IFNγ treatment. Continuous IDO1 blockade by 1-MT but not RU486 treatment normalized the anti-bacterial defense and attenuated increased IL-10 inducibility in splenocytes after repeated stress as it reduced the loss of body weight and behavioral alterations. Moreover, kynurenic acid which remained increased in 1-MT treated repeatedly stressed mice was identified to reduce the TNFα inducibility of splenocytes in vitro and in vivo. Thus, psychological stress stimulates cytokine-driven IDO1 activation and Trp depletion which seems to have a central role for developing stress-induced immunosuppression and behavioral alteration. Since patients showed Trp catabolism already prior to surgery, IDO is also a possible target enzyme for humans modulating immune homeostasis and mood