Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior.

Functional imaging and gene expression studies both implicate the medial prefrontal cortex (mPFC), particularly deep-layer projection neurons, as a potential locus for autism pathology. Here, we explored how specific deep-layer prefrontal neurons contribute to abnormal physiology and behavior in mouse models of autism. First, we find that across three etiologically distinct models-in utero valproic acid (VPA) exposure, CNTNAP2 knockout and FMR1 knockout-layer 5 subcortically projecting (SC) neurons consistently exhibit reduced input resistance and action potential firing. To explore how altered SC neuron physiology might impact behavior, we took advantage of the fact that in deep layers of the mPFC, dopamine D2 receptors (D2Rs) are mainly expressed by SC neurons, and used D2-Cre mice to label D2R+ neurons for calcium imaging or optogenetics. We found that social exploration preferentially recruits mPFC D2R+ cells, but that this recruitment is attenuated in VPA-exposed mice. Stimulating mPFC D2R+ neurons disrupts normal social interaction. Conversely, inhibiting these cells enhances social behavior in VPA-exposed mice. Importantly, this effect was not reproduced by nonspecifically inhibiting mPFC neurons in VPA-exposed mice, or by inhibiting D2R+ neurons in wild-type mice. These findings suggest that multiple forms of autism may alter the physiology of specific deep-layer prefrontal neurons that project to subcortical targets. Furthermore, a highly overlapping population-prefrontal D2R+ neurons-plays an important role in both normal and abnormal social behavior, such that targeting these cells can elicit potentially therapeutic effects

The CaMKII/NMDA receptor complex controls hippocampal synaptic transmission by kinase-dependent and independent mechanisms.

CaMKII is one of the most studied synaptic proteins, but many critical issues regarding its role in synaptic function remain unresolved. Using a CRISPR-based system to delete CaMKII and replace it with mutated forms in single neurons, we have rigorously addressed its various synaptic roles. In brief, basal AMPAR and NMDAR synaptic transmission both require CaMKIIα, but not CaMKIIβ, indicating that, even in the adult, synaptic transmission is determined by the ongoing action of CaMKIIα. While AMPAR transmission requires kinase activity, NMDAR transmission does not, implying a scaffolding role for the CaMKII protein instead. LTP is abolished in the absence of CaMKIIα and/or CaMKIIβ and with an autophosphorylation impaired CaMKIIα (T286A). With the exception of NMDAR synaptic currents, all aspects of CaMKIIα signaling examined require binding to the NMDAR, emphasizing the essential role of this receptor as a master synaptic signaling hub

Author Correction: The CaMKII/NMDA receptor complex controls hippocampal synaptic transmission by kinase-dependent and independent mechanisms.

The originally published version of this Article contained errors in Figure 5, for which we apologise. In panel c, the scatter graph was inadvertently replaced with a scatter graph comprising a subset of data points from panel d. Furthermore, the legends to Figures 5c and 5d were inverted. These errors have now been corrected in both the PDF and HTML versions of the Article, and the incorrect version of Fig. 5c is presented in the Author Correction associated with this Article

CPS Based Liquid Metal Divertor Target for EU-DEMO

AbstractPower exhaust is a key mission in the roadmap to the realization of a future fusion reactor. Among the different solutions, the use of liquid metals as plasma facing materials are of interest due to their potential increased lifetime. Several liquid metal limiters have been successfully tested in the Frascati Tokamak Upgrade over the last 10 years. Liquid materials such as lithium and tin have been investigated using capillary porous systems (CPSs), and their impact on plasma performance has been explored. From such experience, a liquid metal divertor (LMD) concept design, CPS-based, is here proposed. Tin has been preferred as plasma facing material. The proposed LMD would operate, in low evaporative regime, with matching heat exhausting capabilities to those of the baseline ITER-like divertor. Continuous refilling of the CPS is guaranteed with a reservoir at the back of the unit, where the metal is kept liquid through a gas heating circuit. The study has been carried out using ANSYS and the thermal results will be shown. All the design choices are compatible with the current materials and the constraints adopted for the DEMO W divertor. Using such configuration, thermal loads up to 20 MW/m2 are exhausted while keeping the surface temperature below 1250 °C. The design foresees values of pressure, temperature and flow rate of the water coolant in the same range expected for the W DEMO divertor, thus facilitating the integration of such solution in the current cassette design. Technological and practical aspects are addressed, i.e. tin corrosion and CPS wettability. Possible solutions to prevent tin corrosion, and its compatibility with structural materials, will be outlined

Cardiovascular roles of estrogen receptors: insights gained from knockout models

The effects of estrogen are mediated through two functionally distinct receptors, estrogen receptor α (ER- α ), and estrogen receptor β (ER- β ), both of which are expressed in the cardiovascular system. The etiology of cardiovascular disease is believed to result in part from the loss of endogenous estrogen, indicating that estrogen and its receptors may play important roles in the prevention of cardiovascular disease in women

Deuterium retention and erosion in liquid Sn samples exposed to D2 and Ar plasmas in GyM device

The use of tin (Sn) as a liquid metal for plasma facing components has been recently proposed as a solution to the high heat load issue on the divertor target plates in nuclear fusion reactors. Due to its low vapor pressure, low reactivity with hydrogen and good resilience to neutron impact, tin is a good candidate as plasma facing component. However its high atomic number poses concerns about plasma contamination.In this paper two fundamental aspects have been investigated: deuterium retention and erosion fluxes from the Sn surface towards the plasma. The samples were exposed to plasma inside the linear machine GyM in magnetic cusp configuration. This setup permits to expose free liquid specimens without the need for the Capillary Porous System. Moreover it permits to lower the magnetic field in order to increase Sn Larmor radius and consequently limit Sn re-deposition in erosion experiments.Ex-situ analyses by ion beam diagnostics on solid samples exposed to deuterium plasma have proved that the amount of retained atomic deuterium is very low, approximately 0.18 at% estimated by Nuclear Reaction Analysis and 0.25 at% estimated by Elastic Recoil Detection Analysis.In the framework of erosion studies, the spectroscopic parameter S/XB was evaluated in Ar plasma for the SnI line at 380.1 nm by Optical Emission Spectroscopy and mass loss measurements in the 5–11 eV Te range, at a density ne ∼ 1.5 × 1011 cm−3. An average value of 150 ± 23 was obtained. Keywords: Liquid metals, Deuterium retention, Erosion, Double-cusp magnetic configuration, Ion beam diagnostics, S/XB spectroscopic paramete

The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design

<p>Abstract</p> <p>Background</p> <p>Autologous bone marrow-derived stem cells have been ascribed an important therapeutic role in No-Option Critical limb Ischemia (NO-CLI). One primary endpoint for evaluating NO-CLI therapy is major amputation (AMP), which is usually combined with mortality for AMP-free survival (AFS). Only a trial which is double blinded can eliminate physician and patient bias as to the timing and reason for AMP. We examined factors influencing AMP in a prospective double-blinded pilot RCT (2:1 therapy to control) of 48 patients treated with site of service obtained bone marrow cells (BMAC) as well as a systematic review of the literature.</p> <p>Methods</p> <p>Cells were injected intramuscularly in the CLI limbs as either BMAC or placebo (peripheral blood). Six month AMP rates were compared between the two arms. Both patient and treating team were blinded of the assignment in follow-up examinations. A search of the literature identified 9 NO-CLI trials, the control arms of which were used to determine 6 month AMP rates and the influence of tissue loss.</p> <p>Results</p> <p>Fifteen amputations occurred during the 6 month period, 86.7% of these during the first 4 months. One amputation occurred in a Rutherford 4 patient. The difference in amputation rate between patients with rest pain (5.6%) and those with tissue loss (46.7%), irrespective of treatment group, was significant (p = 0.0029). In patients with tissue loss, treatment with BMAC demonstrated a lower amputation rate than placebo (39.1% vs. 71.4%, p = 0.1337). The Kaplan-Meier time to amputation was longer in the BMAC group than in the placebo group (p = 0.067). Projecting these results to a pivotal trial, a bootstrap simulation model showed significant difference in AFS between BMAC and placebo with a power of 95% for a sample size of 210 patients. Meta-analysis of the literature confirmed a difference in amputation rate between patients with tissue loss and rest pain.</p> <p>Conclusions</p> <p>BMAC shows promise in improving AMP-free survival if the trends in this pilot study are validated in a larger pivotal trial. The difference in amp rate between Rutherford 4 & 5 patients suggests that these patients should be stratified in future RCTs.</p

Overview of power exhaust experiments in the COMPASS divertor with liquid metals

Power handling experiments with a special liquid metal divertor module based on the capillary porous system technology were performed in the tokamak COMPASS. The performance of two metals (Li and LiSn alloy) were tested for the first time in a divertor under ELMy H-mode conditions. No damage of the capillary mesh and a good exhaust capability were observed for both metals in two separate experiments with up to 12 MW/m(2) of deposited perpendicular, inter-ELM steady-state heat flux and with ELMs of relative energy similar to 3% and a local peak energy fluence at the module similar to 15 kJ.m(-2). No droplets were directly ejected from the mesh top surface and for the LiSn experiment, no contamination of the core and SOL plasmas by Sn was observed. The elemental depth profile analysis of 14 stainless-steel samples located around the vacuum vessel for each experiment provides information about the migration of evaporated/redeposited liquid elements