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The SPARC tokamak is a high-field, Bt0 ∼12 T, medium-sized, R0 = 1.85 m, tokamak that is presently under construction in Devens, MA, led by Commonwealth Fusion Systems. It will be used to de-risk the high-field tokamak path to a fusion power plant and demonstrate the commercial viability of fusion energy. SPARC's first campaign plan is to achieve Qfus > 1 using an ICRF-heated, <10 MW, high current, Ip ∼ 8.5 MA, L-mode fueled by D-T gas injection, and its second campaign will investigate H-mode operations in D-D. To facilitate plasma control and scientific learning, a targeted set of ∼50 plasma diagnostics are being designed and built for operation during these campaigns. While nearly all diagnostics are based on established techniques, the pace of deployment, relative to the first plasma, and the harshness of the thermal, electromagnetic, and radiation environment are unprecedented for medium-sized tokamaks. An overview of the SPARC diagnostic set is given, providing context to further details communicated by the SPARC team in companion publications that are system-specific. The system engineering philosophy for SPARC diagnostics is outlined, and the design and engineering verification process for components inside and outside the primary vacuum boundary are described. Diagnostics are mounted directly to the vacuum vessel as well as housed within a series of eight midplane and 24 off-midplane replaceable port plugs. With limited exceptions, signal conditioning, digitization electronics and cameras as well as lasers and microwave sources are localized to a series of five Diagnostic Lab spaces, totaling ∼350 m2, located >15 m from the center of the tokamak, on the other side of a 2.4 m concrete shielding wall. A series of 31 large-scale penetrations have been included in the SPARC Tokamak Hall to facilitate integration of early campaign diagnostics and to provide upgradability., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/).)

The path of tokamak fusion and International thermonuclear experimental reactor (ITER) is maintaining high-performance plasma to produce sufficient fusion power. This effort is hindered by the transient energy burst arising from the instabilities at the boundary of plasmas. Conventional 3D magnetic perturbations used to suppress these instabilities often degrade fusion performance and increase the risk of other instabilities. This study presents an innovative 3D field optimization approach that leverages machine learning and real-time adaptability to overcome these challenges. Implemented in the DIII-D and KSTAR tokamaks, this method has consistently achieved reactor-relevant core confinement and the highest fusion performance without triggering damaging bursts. This is enabled by advances in the physics understanding of self-organized transport in the plasma edge and machine learning techniques to optimize the 3D field spectrum. The success of automated, real-time adaptive control of such complex systems paves the way for maximizing fusion efficiency in ITER and beyond while minimizing damage to device components., (© 2024. The Author(s).)

Dravet syndrome is a rare form of severe genetic epilepsy characterized by recurrent and long-lasting seizures. It appears around the first year of life, with a quick evolution toward an increase in the frequency of the seizures, accompanied by a delay in motor and cognitive development, and does not respond well to antiepileptic medication. Most patients carry a mutation in the gene SCN1A encoding the α subunit of the voltage-gated sodium channel Nav1.1, resulting in hyperexcitability of neural circuits and seizure onset. In this work, we applied transcranial static magnetic stimulation (tSMS), a non-invasive, safe, easy-to-use and affordable neuromodulatory tool that reduces neural excitability in a mouse model of Dravet syndrome. We demonstrate that tSMS dramatically reduced the number of crises. Furthermore, crises recorded in the presence of the tSMS were shorter and less intense than in the sham condition. Since tSMS has demonstrated its efficacy at reducing cortical excitability in humans without showing unwanted side effects, in an attempt to anticipate a possible use of tSMS for Dravet Syndrome patients, we performed a numerical simulation in which the magnetic field generated by the magnet was modeled to estimate the magnetic field intensity reached in the cerebral cortex, which could help to design stimulation strategies in these patients. Our results provide a proof of concept for nonpharmacological treatment of Dravet syndrome, which opens the door to the design of new protocols for treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

In a series of high performance diverted discharges on DIII-D, we demonstrate that strong negative triangularity (NT) shaping robustly suppresses all edge-localized mode (ELM) activity over a wide range of plasma conditions: ⟨n⟩=0.1-1.5×10^{20}  m^{-3}, P&#95;{aux}=0-15  MW, and |B&#95;{t}|=1-2.2  T, corresponding to P&#95;{loss}/P&#95;{LH08}∼8. The full dataset is consistent with the theoretical prediction that magnetic shear in the NT edge inhibits access to ELMing H-mode regimes; all experimental pressure profiles are found to be at or below the infinite-n ballooning stability limit. Our present dataset also features edge pressure gradients in strong NT that are closer to an H-mode than a typical L-mode plasma, supporting the consideration of NT for reactor design.

Purpose: There are still many challenges for modelling a thrombus migration process in aneurysms. The main novelty of the present research lies in the modelling of aneurysm clot migration process in a realistic cerebral aneurysm, and the analysis of forces suffered by clots inside an aneurysm, through transient FSI simulations., Methods: The blood flow has been modelled using a Womersley velocity profile, and following the Carreau viscosity model. Hyperelastic Ogden model has been used for clot and isotropic linear elastic model for the artery walls. The FSI coupled model was implemented in ANSYS® software. The hemodynamic forces suffered by the clot have been quantified using eight different clot sizes and positions inside a real aneurysm., Results: The obtained results have shown that it is almost impossible for clots adjacent to aneurysm walls, to leave the aneurysm. Nevertheless, in clots positioned in the centre of the aneurysm, there is a real risk of clot migration. The risk of migration of a typical post-coiling intervention clot in an aneurysm, in contact with the wall and occupying a significant percentage of its volume is very low in the case studied, even in the presence of abnormally intense events, associated with sneezes or impacts., Conclusions: The proposed methodology allows evaluating the clot migration risk, vital for evaluating the progress after endovascular interventions, it is a step forward in the personalized medicine, patient follow-up, and helping the medical team deciding the optimal treatment., (© 2023. The Author(s).)

Experiments on the DIII-D tokamak have identified a novel regime in which applied resonant magnetic perturbations (RMPs) increase the particle confinement and overall performance. This Letter details a robust range of counter-current rotation over which RMPs cause this density pump-in effect for high confinement (H mode) plasmas. The pump in is shown to be caused by a reduction of the turbulent transport and to be correlated with a change in the sign of the induced neoclassical transport. This novel reversal of the RMP induced transport has the potential to significantly improve reactor relevant, three-dimensional magnetic confinement scenarios.

The Gamma Ray Imager (GRI) is a pinhole camera providing 2D imaging of MeV hard x-ray (HXR) bremsstrahlung emission from runaway electrons (REs) over the poloidal cross section of the DIII-D tokamak. We report a series of upgrades to the GRI expanding the access to RE scenarios from the diagnosis of a trace amount of REs to high flux HXR measurements during the RE plateau phase. We present the implementation of novel gamma ray detectors based on LYSO and YAP crystals coupled to multi-pixel photon counters, enabling a count rate in excess of 1 MHz. Finally, we highlight new insights into the RE physics discovered during the current quench and RE plateau phase experiments as the result of these upgrades.

Background: Psychological interventions are commonly used to treat mild-to-moderate depression, but their efficacy in young adults has not been exhaustively addressed. This meta-analysis aims to establish it in comparison to no treatment, wait-list, usual treatment, passive interventions, and other bona-fide treatments., Methods: The search was conducted in Scopus, MEDLINE, PsycINFO, ClinicalTrials.gov, the ISRCTN Registry, Cochrane CENTRAL, Clarivate BIOSIS Previews and the METAPSY database, retrieving studies from the start of records to April 2020. Eligibility criteria included samples of 16-30 years experiencing mild-to-moderate depressive symptoms and participating in randomized controlled trials (RCTs), non-RCTs, or pre-post studies measuring depressive symptomatology and featuring psychological treatments., Results: Up to 45 studies met criteria, consisting of 3,947 participants, assessed using the Quality Assessment Tool for Quantitative Studies and their results meta-analyzed assuming random effects. Psychological interventions proved to be efficacious in RCTs compared to no treatment (g = -0.68; 95% CI = -0.87, -0.48) and wait-list (g = -1.04; 95% CI = -1.25, -0.82), while depressive symptoms also improved in pre-post studies (g = -0.99; 95% CI = -1.32, -0.66). However, intervention efficacy was similar to usual care, passive, and bona-fide comparators. The heterogeneity found, a likely reporting bias and the low quality of most studies must be considered when interpreting these results., Conclusions: Psychological treatments are efficacious to reduce depressive symptoms in young adults, but comparable to other interventions in the mild-to-moderate range. Moderators like depression severity or therapist involvement significantly influenced their efficacy, with results encouraging clinicians to adopt flexible and personalized approaches., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objective: The attainment of a methodology to simulate the hemodynamic in patient-specific cerebral vessels with aneurysms is still a challenge. The novelty of this work is focused on the effect of coil embolization in a realistic cerebral aneurysm, according to the vessel wall thickness and aneurysm thickness, through transient FSI simulations., Methods: The quality of the mesh for simulations was checked with a specific mesh convergence study; and the numerical methodology was validated using numerical research data of the literature. The model was implemented in ANSYS® software. The total deformation and equivalent stress evolution in the studied cases, before and after coil embolization, were compared. More than 20 different models were employed due to different arterial wall thickness and aneurysm wall thickness combinations., Results: The obtained results have showed that deformation and stress values are highly influenced with the sac thickness. The thinner sac aneurysm thickness is, the greater deformation and stress are. The results after coil embolization process have highlighted that considering typical values of arterial wall thickness and aneurysm thickness 0.3 mm and 0.15 mm respectively, a deformation reduction around 50% and a stress reduction around 70% can be achieved., Conclusions: The proposed methodology is a step forward in the personalized medicine, quantifying the aneurysm rupture risk reduction, and helping the medical team in the preoperative planning, or to deciding the optimal treatment., Competing Interests: Declaration of Competing Interest Authors declare that they have not any actual or potential conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

A novel compact spectrometer optimized for the measurement of hard x rays generated by runaway electrons is presented. The detector is designed to be installed in the fan-shaped collimator of the gamma-ray imager diagnostic at the DIII-D tokamak. The spectrometer is based on a 1 × 1 cm 2 cerium doped yttrium aluminum perovskite scintillator crystal coupled with a silicon photomultiplier. The detector dynamic energy range is in excess of 10 MeV, with an energy resolution of ∼10% at 661.7 keV. The fast detector signal (≈70 ns full width at half maximum) allows for operation at counting rates in excess of 1 MCps. The gain stability of the system can be monitored in real time using a light-emitting diode embedded in the instrument. The detector is expected to be deployed in the forthcoming DIII-D runaway electron experimental campaign.

Predictive 3D optimization reveals a novel approach to modify a nonaxisymmetric magnetic perturbation to be entirely harmless for tokamaks, by essentially restoring quasisymmetry in perturbed particle orbits as much as possible. Such a quasisymmetric magnetic perturbation (QSMP) has been designed and successfully tested in the KSTAR and DIII-D tokamaks, demonstrating no performance degradation despite the large overall amplitudes of nonaxisymmetric fields and strong response otherwise expected in the tested plasmas. The results indicate that a quasisymmetric optimization is a robust path of error field correction across the resonant and nonresonant field spectrum in a tokamak, leveraging the prevailing concept of quasisymmetry for general 3D plasma confinement systems such as stellarators. The optimization becomes, in fact, a simple eigenvalue problem to the so-called torque response matrices if a perturbed equilibrium is calculated consistent with nonaxisymmetric neoclassical transport.

Disturbances in personal identity are recognized in psychosis and depression. However, it is unknown whether these disruptions share common processes across clinical groups, or whether there are unique alterations by group or between men and women within each clinical group. To advance on this question, we compared personal identity dimensions in psychosis and depression and investigated the effects of gender and depressive mood. This study assessed dimensions of personal identity using the repertory grid technique among 85 outpatients with psychosis, 85 outpatients with depressive disorders and 85 healthy controls who were matched by age. Data regarding depressive mood and general functioning was also collected. Results showed that self-discrepancies were higher in psychosis and depression than in controls, and were associated with depressive mood. Interpersonal dichotomous thinking was more prevalent in women in both clinical groups. Women with psychosis showed higher ideal-others discrepancy and had a more complex structure of personal identity than their male counterparts. To conclude, alterations in self-ideal and self-others discrepancies may be transdiagnostic dimensions related to depressive mood. Interpersonal dichotomous thinking may also be a common dimensional characteristic in psychosis and depression but more specific to women. Finally, critical views of others and a higher complexity of personal identity may be more specific to women than men with psychosis. Our results are consistent with other studies pointing to the need for person-focused treatments promoting the recovery of a full sense of personal identity, rather than just focusing on specific thoughts and feelings., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Edge-localized mode (ELM) suppression by resonant magnetic perturbations (RMPs) generally occurs over very narrow ranges of the plasma current (or magnetic safety factor q&#95;{95}) in the DIII-D tokamak. However, wide q&#95;{95} ranges of ELM suppression are needed for the safety and operational flexibility of ITER and future reactors. In DIII-D ITER similar shape plasmas with n=3 RMPs, the range of q&#95;{95} for ELM suppression is found to increase with decreasing electron density. Nonlinear two-fluid MHD simulations reproduce the observed q&#95;{95} windows of ELM suppression and the dependence on plasma density, based on the conditions for resonant field penetration at the top of the pedestal. When the RMP amplitude is close to the threshold for resonant field penetration, only narrow isolated magnetic islands form near the top of the pedestal, leading to narrow q&#95;{95} windows of ELM suppression. However, as the threshold for field penetration decreases with decreasing density, resonant field penetration can take place over a wider range of q&#95;{95}. For sufficiently low density (penetration threshold) multiple magnetic islands form near the top of the pedestal giving rise to continuous q&#95;{95} windows of ELM suppression. The model predicts that wide q&#95;{95} windows of ELM suppression can be achieved at substantially higher pedestal pressure in DIII-D by shifting to higher toroidal mode number (n=4) RMPs.

DIII-D experiments at low density (n&#95;{e}∼10^{19}  m^{-3}) have directly measured whistler waves in the 100-200 MHz range excited by multi-MeV runaway electrons. Whistler activity is correlated with runaway intensity (hard x-ray emission level), occurs in novel discrete frequency bands, and exhibits nonlinear limit-cycle-like behavior. The measured frequencies scale with the magnetic field strength and electron density as expected from the whistler dispersion relation. The modes are stabilized with increasing magnetic field, which is consistent with wave-particle resonance mechanisms. The mode amplitudes show intermittent time variations correlated with changes in the electron cyclotron emission that follow predator-prey cycles. These can be interpreted as wave-induced pitch angle scattering of moderate energy runaways. The tokamak runaway-whistler mechanisms have parallels to whistler phenomena in ionospheric plasmas. The observations also open new directions for the modeling and active control of runaway electrons in tokamaks.

This study aims to establish the current state of the IT-15 (HTT) gene in different Ecuadorian ethnic groups and patients by determining CAG triplet repeats, compared with the ethnicity of individuals. A total of 412 individuals were studied using nested polymerase chain reaction and Sanger sequencing: 75 individuals were indigenous (Kichwas), 211 mestizos, and 65 Afro-Ecuadorians. We included 31 patients who were clinically diagnosed with Huntington's disease (HD) and relatives of the affected patients (n = 30). Moreover, we correlated the presence of HD in Ecuadorian patients with 46 genetic ancestry-informative insertion-deletion polymorphic markers. We found that 77.20% had <28 CAG repetitions, 18.80% had mutable alleles, 2.27% had incomplete penetrance, and 1.70% reflected >39 repetitions. The average of CAG repetitions was 24 ± 3 for indigenous people; 28 ± 2 for mestizos; and 24 ± 3.2 repetitions for the Afro-Ecuadorians. The ancestral component showed that the main ancestry corresponded to Native Americans (0.873) and European ascendants (0.145), Africans were less represented in the evaluated population (0.018). There was a significant difference between the number of CAG repeats in mestizos and indigenous people (P < .01), suggesting that the Ecuadorian mestizo population has a risk factor for the gene mutation., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Novel spatial, temporal, and energetically resolved measurements of bremsstrahlung hard-x-ray (HXR) emission from runaway electron (RE) populations in tokamaks reveal nonmonotonic RE distribution functions whose properties depend on the interplay of electric field acceleration with collisional and synchrotron damping. Measurements are consistent with theoretical predictions of momentum-space attractors that accumulate runaway electrons. RE distribution functions are measured to shift to a higher energy when the synchrotron force is reduced by decreasing the toroidal magnetic field strength. Increasing the collisional damping by increasing the electron density (at a fixed magnetic and electric field) reduces the energy of the nonmonotonic feature and reduces the HXR growth rate at all energies. Higher-energy HXR growth rates extrapolate to zero at the expected threshold electric field for RE sustainment, while low-energy REs are anomalously lost. The compilation of HXR emission from different sight lines into the plasma yields energy and pitch-angle-resolved RE distributions and demonstrates increasing pitch-angle and radial gradients with energy.

The Kaposi's Sarcoma-associated Herpes virus G Protein-Coupled Receptor (vGPCR) is a key molecule in the pathogenesis of Kaposi Sarcoma. We have previously demonstrated that the proteasome inhibitor Bortezomib inhibits NF-κB pathway, which is required for tumor maintenance in endothelial cells that express vGPCR (vGPCR cells). In this work, we further investigated Bortezomib anti-proliferative mechanism of action. We demonstrated that Bortezomib decreases vGPCR cell number in a dose-dependent manner and induces cell morphology changes. Bortezomib decreases ERK1/2 phosphorylation whereas induces the accumulation of MKP-3 - a specific ERK1/2 MAP kinase phosphatase - in time and concentration dependent manner (1.5-32h; 0.25-1nM). The transcription factor FOXO1 is activated by dephosphorylation and regulates p21 expression. Here, we demonstrated that Bortezomib increases FOXO1 protein and decreases its phosphorylation in a concentration dependent manner (0.25-1nM). Bortezomib (0.5nM, 24h) also increase nuclear FOXO1 protein, in line with FOXO1 dephosphorylation induced by the drug. Consistent with FOXO1 dephosphorylation/activation, p21 mRNA expression is increased by Bortezomib in a MKP-3-dependent way. Bortezomib (0.5nM, 24h) also decreases VEGF, an ERK1/2 -dependent effect. It is concluded that in vGPCR cells, Bortezomib decreases ERK1/2 and FOXO1 phosphorylation through MKP-3 accumulation, leading ERK1/2 deactivation and FOXO1 activation respectively and, consequently, to cell proliferation inhibition, p21 induction and VEGF repression. Taken together, all these events contribute to the anti-tumoral effect of Bortezomib., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A new gamma ray imager (GRI) is developed to probe the electron distribution function with 2D spatial resolution during runaway electron (RE) experiments at the DIII-D tokamak. The diagnostic is sensitive to 0.5-100 MeV gamma rays, allowing characterization of the RE distribution function evolution during RE growth and dissipation. The GRI consists of a lead "pinhole camera" mounted on the DIII-D midplane with 123 honeycombed tangential chords 20 cm wide that span the vessel interior. Up to 30 bismuth germanate (BGO) scintillation detectors capture RE bremsstrahlung radiation for Pulse Height Analysis (PHA) capable of discriminating up to 20 000 pulses per second. Digital signal processing routines combining shaping filters are performed during PHA to reject noise and record gamma ray energy. The GRI setup and PHA algorithms will be described and initial data from experiments will be presented. A synthetic diagnostic is developed to generate the gamma ray spectrum of a GRI channel given the plasma information and a prescribed distribution function. Magnetic reconstructions of the plasma are used to calculate the angle between every GRI sightline and orient and discriminate gamma rays emitted by a field-aligned RE distribution function.

New evidence indicates that there is significant 3D variation in density fluctuations near the boundary of weakly 3D tokamak plasmas when resonant magnetic perturbations are applied to suppress transient edge instabilities. The increase in fluctuations is concomitant with an increase in the measured density gradient, suggesting that this toroidally localized gradient increase could be a mechanism for turbulence destabilization in localized flux tubes. Two-fluid magnetohydrodynamic simulations find that, although changes to the magnetic field topology are small, there is a significant 3D variation of the density gradient within the flux surfaces that is extended along field lines. This modeling agrees qualitatively with the measurements. The observed gradient and fluctuation asymmetries are proposed as a mechanism by which global profile gradients in the pedestal could be relaxed due to a local change in the 3D equilibrium. These processes may play an important role in pedestal and scrape-off layer transport in ITER and other future tokamak devices with small applied 3D fields.

Low-complexity regions are sub-sequences of biased composition in a protein sequence. The influence of these regions over protein evolution, specific functions and highly interactive capacities is well known. Although protein sequence entropy has been largely studied, its relationship with low-complexity regions and the subsequent effects on protein function remains unclear. In this work we propose a theoretical and empirical model integrating the sequence entropy with local complexity parameters. Our results indicate that the protein sequence entropy is related with the protein length, the entropies inside and outside the low-complexity regions as well as their number and average size. We found a small but significant increment in the sequence entropy of hubs proteins. In agreement with our theoretical model, this increment is highly dependent of the balance between the increment of protein length and average size of the low-complexity regions. Finally, our models and proteins analysis provide evidence supporting that modifications in the average size is more relevant in hubs proteins than changes in the number of low-complexity regions., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Amphibian populations are decreasing worldwide due to a variety of factors. In South America, the chytrid fungus Batrachochytrium dendrobatidis (Bd) is linked to many population declines. The pathogenic effect of Bd on amphibians can be inhibited by specific bacteria present on host skin. This symbiotic association allows some amphibians to resist the development of the disease chytridiomycosis. Here, we aimed (1) to determine for the first time if specific anti-Bd bacteria are present on amphibians in the Andes of Ecuador, (2) to monitor anti-Bd bacteria across developmental stages in a focal amphibian, the Andean marsupial tree frog, Gastrotheca riobambae, that deposits larvae in aquatic habitats, and (3) to compare the Bd presence associated with host assemblages including 10 species at sites ranging in biogeography from Amazonian rainforest (450 masl) to Andes montane rainforest (3200 masl). We sampled and identified skin-associated bacteria of frogs in the field using swabs and a novel methodology of aerobic counting plates, and a combination of morphological, biochemical, and molecular identification techniques. The following anti-Bd bacteria were identified and found to be shared among several hosts at high-elevation sites where Bd was present at a prevalence of 32.5%: Janthinobacterium lividum, Pseudomonas fluorescens, and Serratia sp. Bd were detected in Gastrotheca spp. and not detected in the lowlands (sites below 1000 masl). In G. riobambae, recognized Bd-resistant bacteria start to be present at the metamorphic stage. Overall bacterial abundance was significantly higher post-metamorphosis and on species sampled at lower elevations. Further metagenomic studies are needed to evaluate the roles of host identity, life-history stage, and biogeography of the microbiota and their function in disease resistance.

Density pumpout and edge-localized mode (ELM) suppression by applied n=2 magnetic fields in low-collisionality DIII-D plasmas are shown to be correlated with the magnitude of the plasma response driven on the high-field side (HFS) of the magnetic axis but not the low-field side (LFS) midplane. These distinct responses are a direct measurement of a multimodal magnetic plasma response, with each structure preferentially excited by a different n=2 applied spectrum and preferentially detected on the LFS or HFS. Ideal and resistive magneto-hydrodynamic (MHD) calculations find that the LFS measurement is primarily sensitive to the excitation of stable kink modes, while the HFS measurement is primarily sensitive to resonant currents (whether fully shielding or partially penetrated). The resonant currents are themselves strongly modified by kink excitation, with the optimal applied field pitch for pumpout and ELM suppression significantly differing from equilibrium field alignment.

Rapid bifurcations in the plasma response to slowly varying n=2 magnetic fields are observed as the plasma transitions into and out of edge-localized mode (ELM) suppression. The rapid transition to ELM suppression is characterized by an increase in the toroidal rotation and a reduction in the electron pressure gradient at the top of the pedestal that reduces the perpendicular electron flow there to near zero. These events occur simultaneously with an increase in the inner-wall magnetic response. These observations are consistent with strong resonant field penetration of n=2 fields at the onset of ELM suppression, based on extended MHD simulations using measured plasma profiles. Spontaneous transitions into (and out of) ELM suppression with a static applied n=2 field indicate competing mechanisms of screening and penetration of resonant fields near threshold conditions. Magnetic measurements reveal evidence for the unlocking and rotation of tearinglike structures as the plasma transitions out of ELM suppression.

The DIII-D tokamak magnetic diagnostic system [E. J. Strait, Rev. Sci. Instrum. 77, 023502 (2006)] has been upgraded to significantly expand the measurement of the plasma response to intrinsic and applied non-axisymmetric "3D" fields. The placement and design of 101 additional sensors allow resolution of toroidal mode numbers 1 ≤ n ≤ 3, and poloidal wavelengths smaller than MARS-F, IPEC, and VMEC magnetohydrodynamic model predictions. Small 3D perturbations, relative to the equilibrium field (10(-5) < δB/B0 < 10(-4)), require sub-millimeter fabrication and installation tolerances. This high precision is achieved using electrical discharge machined components, and alignment techniques employing rotary laser levels and a coordinate measurement machine. A 16-bit data acquisition system is used in conjunction with analog signal-processing to recover non-axisymmetric perturbations. Co-located radial and poloidal field measurements allow up to 14.2 cm spatial resolution of poloidal structures (plasma poloidal circumference is ~500 cm). The function of the new system is verified by comparing the rotating tearing mode structure, measured by 14 BP fluctuation sensors, with that measured by the upgraded B(R) saddle loop sensors after the mode locks to the vessel wall. The result is a nearly identical 2/1 helical eigenstructure in both cases.

Helicobacter pylori (Hp) has a worldwide distribution showing its higher prevalence of infection in developing countries. Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) are proteins that recognize pathogen-associated molecular patterns (PAMPs) and initiate an innate immune response by promoting growth and differentiation of specialized hematopoietic cells for host defense. Gastric infections led by Hp induce a Th-1 cellular immune response, regulated mainly by the expression of IFN-γ. In this retrospective case-control study, we evaluated the TLR1 1805T/G, TLR2 2029C/T, TLR4 896A/G, CD209 -336A/G and IFNGR1 -56C/T polymorphisms and their relationship with susceptibility to Hp infection. TLR1 1805T/G showed statistical differences when the control (Hp-) and infected (Hp+) groups (P = 0.041*) were compared; the TLR1 1805G allele had a protective effect towards infection (OR = 0.1; 95% CI = 0.01-0.88, P = 0.033*). Similarly, the IFNGR1 -56C/T polymorphism showed statistical differences between Hp+ and Hp- (P = 0.018*), and the IFNGR1 -56TT genotype exhibited significant risk to Hp infection (OR = 2.9, 95% CI = 1.27-6.54, P = 0.018*). In conclusion, the pro-inflammatory TLR1 1805T and IFNGR1 -56T alleles are related with susceptibility to Hp infection in Ecuadorian individuals. The presence of these polymorphisms in individuals with chronic infection increases the risk of cellular damage and diminishes the cellular immune response efficiency towards colonizing agents., (© 2014 John Wiley & Sons Ltd.)

Magnetic feedback control of the resistive-wall mode has enabled the DIII-D tokamak to access stable operation at safety factor q(95) = 1.9 in divertor plasmas for 150 instability growth times. Magnetohydrodynamic stability sets a hard, disruptive limit on the minimum edge safety factor achievable in a tokamak, or on the maximum plasma current at a given toroidal magnetic field. In tokamaks with a divertor, the limit occurs at q(95) = 2, as confirmed in DIII-D. Since the energy confinement time scales linearly with current, this also bounds the performance of a fusion reactor. DIII-D has overcome this limit, opening a whole new high-current regime not accessible before. This result brings significant possible benefits in terms of fusion performance, but it also extends resistive-wall mode physics and its control to conditions never explored before. In present experiments, the q(95) < 2 operation is eventually halted by voltage limits reached in the feedback power supplies, not by intrinsic physics issues. Improvements to power supplies and to control algorithms have the potential to further extend this regime.

Objective: To identify variables associated with early nasal continuous positive airway pressure (ENCPAP) failure in preterm neonates less than 30 weeks gestational age., Study Design: Multicenter prospective study including 131 preterm newborns, over a period of 2 years. Patients and respiratory variables were assessed using univariate analysis., Result: Variables associated with ENCPAP failure were: the need of resuscitation with a FiO(2)>0.30; a CPAP pressure of 6.4±1.2 cm H(2)O; the need of a FiO(2) of 0.40 in the first 4 h of life; male gender maintaining the need of a FiO(2)>0.25 in the first 4 h of life; and respiratory distress syndrome with criteria for surfactant administration., Conclusion: The need for oxygen in resuscitation and maintained in first hours of life, male gender, a CPAP pressure over 5 cm H(2)O and surfactant need are predictors of ENCPAP failure in preterm neonates 26 to 30 weeks gestational age.

Stabilization of the resistive wall mode (RWM) by high-speed differentially rotating conducting walls is demonstrated in the laboratory. To observe stabilization intrinsic azimuthal plasma rotation must be braked with error fields. Above a critical error field the RWM frequency discontinuously slows (locks) and fast growth subsequently occurs. Wall rotation is found to reduce the locked RWM saturated amplitude and growth rate, with both static (vacuum vessel) wall locked and slowly rotating RWMs observed depending on the alignment of wall to plasma rotation. At high wall rotation RWM onset is found to occur at larger plasma currents, thus increasing the RWM-stable operation window.

Several reports suggest putative interactions between valproic acid (VPA) treatment and the hypothalamus-pituitary-adrenal axis. Given that VPA alters mitochondrial functions, an action of this drug on a mitochondrial process such as steroid synthesis in adrenal cells should be expected. In order to disclose a putative action of VPA on the adrenocortical cell itself we evaluated VPA effects on regulatory steps of the acute stimulation of steroidogenesis in Y1 adrenocortical cells. This study demonstrates that VPA increases progesterone production in non-stimulated cells without inducing the levels of Steroidogenic Acute Regulatory (StAR) protein, which facilitates cholesterol transport. This result suggests that VPA increases mitochondrial cholesterol transport through a StAR-independent mechanism and is further supported by the fact that in isolated mitochondria VPA stimulates exogenous cholesterol metabolization to progesterone. VPA also reduces the cAMP-mediated increase of the StAR protein, mRNA levels, promoter activity and progesterone production. In summary, the present data show that VPA can alter steroid production in adrenal cells by a complex mechanism that mainly involves an action on cholesterol access to the inner mitochondrial membrane. The VPA-mediated increase of basal steroidogenesis could be linked to the increase of basal cortisolemia described in patients under VPA treatment., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The rotating wall machine, a basic plasma physics experimental facility, has been constructed to study the role of electromagnetic boundary conditions on current-driven ideal and resistive magnetohydrodynamic instabilities, including differentially rotating conducting walls. The device, a screw pinch magnetic geometry with line-tied ends, is described. The plasma is generated by an array of 19 plasma guns that not only produce high density plasmas but can also be independently biased to allow spatial and temporal control of the current profile. The design and mechanical performance of the rotating wall as well as diagnostic capabilities and internal probes are discussed. Measurements from typical quiescent discharges show the plasma to be high β (≤p>2μ(0)/B(z)(2)), flowing, and well collimated. Internal probe measurements show that the plasma current profile can be controlled by the plasma gun array.

Background: Bowlby developed the concept of 'caregiver' to refer to significant adults with whom young children interact daily. Not only parents are considered significant caregivers but also the care centre staff where the child attends regularly. Within caregiver-infant interactions, sensitive response on the part of the adult is a key concept in the assessment of the quality of the relationship, as it integrates the experiences and emotions that will influence the attainment of a secure attachment and a favourable emotional, social and cognitive development in the child., Methods: This study is a comparative analysis between the dyadic interactions between a child and its principal caregivers in the home and in the crèche; it is based on a group of 185 children between 8 and 24 months old, who attend a crèche regularly. The Care-Index instrument was used to assess interaction between children and adults, analysing sensitive response in the adults and cooperativeness in the children., Results: The sensitive response of adults to children was complementary; mothers and primary caregivers showed greater sensitivity in the affective aspects of the interaction, while the care centre staff showed greater sensitivity in the cognitive aspects. The fact that caregivers show significant differences in response sensitivity is consistent with existing studies, as are corresponding significant differences in the children's cooperativeness, which demonstrates that a child could benefit from interacting with adults whose different skills could strengthen diverse aspects of health child development., Conclusions: The presence of children in the crèche can be a positive experience in that it favours quality exchanges with the child, developing cognitive aspects of the interaction which are cultivated to a lesser degree by mothers or primary caregivers who principally develop affective aspects.

Two miniature pinhole camera arrays for spatially and temporally resolved measurements of soft x-ray emission have been designed and installed on the STOR-M tokamak. Each array consists of a photodiode array, with one array viewing vertically and one viewing horizontally through a plasma cross section. Preamplifiers with fixed gains of 10(5) VA and custom built amplifiers with variable gains are used for signal amplification. Digitizers with 14 bit resolution and 3 MSs sampling rate are used for data acquisition. In the initial operation, an Al foil with a thickness of 1.8 microm installed for one array and Be filter of 7.6 microm installed for the other array are used to test signal strength. Initial tests have identified sawtooth oscillations and 20 kHz fluctuations, which are also detected by Mirnov coils, superimposed on the sawtooth oscillations.

Stimulation of receptors and subsequent signal transduction results in the activation of arachidonic acid (AA) release. Once AA is released from phospholipids or others esters, it may be metabolized via the cycloxygenase or the lipoxygenase pathways. How the cells drive AA to these pathways is not elucidated yet. It is reasonable to speculate that each pathway will have different sources of free AA triggered by different signal transduction pathways. Several reports have shown that AA and its lipoxygenase-catalyzed metabolites play essential roles in the regulation of steroidogenesis by influencing cholesterol transport from the outer to the inner mitochondrial membrane, the rate-limiting step in steroid hormone biosynthesis. Signals that stimulate steroidogenesis also cause the release of AA from phospholipids or other esters by mechanisms that are not fully understood. This review focuses on the enzymes of AA release that impact on steroidogenesis.

Circadian clocks are widely distributed in mammalian tissues, but little is known about the physiological functions of clocks outside the suprachiasmatic nucleus of the brain. The retina has an intrinsic circadian clock, but its importance for vision is unknown. Here, we show that mice lacking Bmal1, a gene required for clock function, had abnormal retinal transcriptional responses to light and defective inner retinal electrical responses to light, but normal photoreceptor responses to light and retinas that appeared structurally normal as observed by light and electron microscopy. We generated mice with a retina-specific genetic deletion of Bmal1, and they had defects of retinal visual physiology essentially identical to those of mice lacking Bmal1 in all tissues and lacked a circadian rhythm of inner retinal electrical responses to light. Our findings indicate that the intrinsic circadian clock of the retina regulates retinal visual processing in vivo.

Maternal Education can be considered one of Primary Health Care Midwives' most specific and exclusive activities. From its beginning, its objective concerned reducing pain and improving one's preparation for childbirth. However due to the changes in women's lifestyles and in obstetrics practices, especially with the introduction of epidural anesthesia, midwives have been obliged to revise this objective and the achievements obtained with this task. An analysis of women's needs and of which information is the most effective will enable midwives to update and distribute their resources and finally optimize the results of their services.

The expression pattern of pannexin1, a gene coding for a protein that forms gap junction channels, was studied as both mRNA and protein in the CNS of adult mouse. Pannexin1 was widely expressed in the CNS by neuronal cell types but not glial cells, except for Bergmann glial cells of the cerebellar cortex. Cells positive to Ca-binding proteins, principally parvalbumin, but also calbindin and calretinin, as well as glutamate decarboxylase 67 kDa isoform, were pannexin1-positive. Pannexin1 labeling was found in cells which are known to exhibit spontaneous and synchronous discharge, such as neurons of the inferior olivary complex and the reticular thalamic nucleus, and also in neurons whose electrical activity is not coupled with neighboring cells, such as motoneurons of the spinal cord. The analysis of cellular localization showed puncta that surrounded cell bodies (e.g. the pyramidal cells of hippocampus) or restricted areas inside the cell bodies (e.g. the spinal motoneurons). In Bergmann glial cells the staining was present as fine grains that covered a large part of the cellular surface. Pannexin1 stained cells that previous studies have reported as expressing connexin36, another protein forming gap junction channels. Thus, it was possible that these two proteins could be integrated in the same functions. Since connexin36 expression levels change after seizures, we examined the expression of both pannexin1 and connexin36 in cerebral cortex, hippocampus, cerebellum and brain stem at different time intervals (2, 4 and 8 h) after i.p. injection of 4-aminopyridine, which resulted in systemic seizures. The only modification of the expression levels observed in this study concerned the progressive decrement of the connexin36 in the hippocampus, while pannexin1 expression was unchanged. This finding suggested that pannexin1 and connexin36 are involved in different functional roles or that they are expressed in different cell types and that only those expressing the Cx36 are induced to apoptosis by epileptic seizures.

Although the role of arachidonic acid (AA) in trophic hormone-stimulated steroid production in various steroidogenic cells is well documented, the mechanism responsible for AA release remains unknown. We have previously shown evidence of an alternative pathway of AA generation in steroidogenic tissues. Our results are consistent with the hypothesis that, in steroidogenic cells, AA is released by the action of a mitochondrial acyl-CoA thioesterase (MTE-I). We have shown that recombinant MTE-I hydrolyses arachidonoyl-CoA to release free AA. An acyl-CoA synthetase specific for AA, acyl-CoA synthetase 4, has also been described in steroidogenic tissues. In the present study we investigate the new concept in the regulation of intracellular levels of AA, in which trophic hormones can release AA by mechanisms different from the classical PLA2-mediated pathway. Inhibition of ACS4 and MTE-I activity by triacsin C and NDGA, respectively results in a reduction of StAR mRNA and protein abundance. When both inhibitors are added together there is a synergistic effect in the inhibition of StAR mRNA, StAR protein levels and ACTH-stimulated steroid synthesis. The inhibition of steroidogenesis produced by the NDGA and triacsin C can be overcome by the addition of exogenous AA. In summary, results shown here demonstrate a critical role of the acyl-CoA synthetase and the acyl-CoA thioesterase in the regulation of AA release, StAR induction, and steroidogenesis. This further suggests a new concept in the regulation of intracellular distribution of AA through a mechanism different from the classical PLA2-mediated pathway that involves a hormone-induced acyl-CoA synthetase and a hormone-regulated acyl-CoA thioesterase.

Several stimuli, including stress conditions, promote the activation of MAP kinases family members (ERK1/2, JNK, p38). In turn, these enzymes regulate several cellular functions. Given that MAPK activation requires the phosphorylation of these proteins, their inactivation depends on the activity of specific phosphatases. MAPK phosphatase-1 (MKP-1), a phosphatase specifically involved in the inactivation of MAPK family members, is induced by mitogenic stimuli and stress conditions. Here we describe the effect of heat shock (HS), 10 min, 45 degrees C, on MAPKs activities and MKP-1 mRNA and protein levels in Y1 adrenocortical cells. Western blot analysis performed with antibodies against the phosphorylated forms of ERK1/2 and JNK revealed that HS produced the rapid activation of these kinases. Their inactivation was also a rapid event and occurred together with the increase of MKP-1 protein levels detected by Western blot analysis. In addition, the effect of HS on MKP-1 protein levels seems to be exerted at the transcriptional level, since the amount of its mRNA in heat shocked cells was higher than in nonheated cells. Comparison of the temporal profiles of MKP-1 protein induction and MAPKs phospho-dephosphorylation suggests that MKP-1 induction could contribute to ERK1/2 and JNK inactivation after HS.

The LH signal transduction pathway features the activation of protein tyrosine phosphatases (PTPs) as one of the components of a cascade that includes other well characterized events such as cAMP-dependent protein kinase A (PKA) activation. Moreover, the action of PTPs is required to increase the rate-limiting step in steroid biosynthesis, namely the cAMP-regulated transfer of cholesterol to the inner mitochondrial membrane. Since both PKA activity and steroidogenic acute regulatory (StAR) protein induction are obligatory steps in this transfer of cholesterol, the present study was performed to investigate the role of PTPs in the regulation of PKA activity and StAR expression in response to LH/chorionic gonadotropin (CG) and 8Br-cAMP in MA-10 cells. While the exposure of MA-10 cells to the PTP inhibitor, phenylarsine oxide (PAO), did not modify PKA activity, it partially inhibited the effect of human CG and cAMP analog on StAR protein levels. Time-course studies demonstrated that PAO inhibited cAMP induction of StAR protein and mRNA. At 30 min, the effect on cAMP-stimulated StAR protein levels was a 35% inhibition, progressing to up to 90% inhibition at 120 min of stimulation. The maximal inhibitory effect on cAMP-induced StAR mRNA level was obtained at 60 min (85%). In summary, these results demonstrate that inhibition of PTP activity affected both StAR protein and mRNA synthesis and suggest that the activity of hormone-regulated PTPs is a requirement in the LH signaling cascade that results in the up-regulation of StAR protein and, subsequently, increased steroid synthesis.

A key regulatory step in the steroidogenic hormones signaling pathway is the synthesis of steroidogenic acute regulatory protein (StAR). This protein facilitates the delivery of cholesterol to the inner mitochondrial membrane, the rate-limiting step in steroidogenesis. ACTH and LH pathway also includes tyrosine dephosphorylation processes. Indeed, our previous studies have demonstrated that both hormones increase protein tyrosine phosphatase (PTP) activity by a PKA-dependent mechanism and that the action of PTPs is required for the stimulation of steroid biosynthesis in adrenal and Leydig cells. In order to test the putative relationship between PTP activity and StAR protein induction in adrenocortical cells, in the present study we evaluated steroid production and StAR protein level in Y1 adrenocortical cells under PTP inhibition. Phenylarsine oxide (PAO), a powerful cell permeable PTP inhibitor, reduced ACTH-stimulated steroidogenesis in a concentration-dependent fashion. A concentration of 2.5 microM of this compound inhibited steroid synthesis in a 56% (ACTH = 318 +/- 30, ACTH + PAO = 145 +/- 18 ng progesterone/mL, P < 0.001) and also abrogated StAR protein induction. Phenylarsine oxide reduced the protein level after 60 min and this effect still remained at 120 min. A second PTP inhibitor, benzyl phosphonic acid, acting by a different mechanism, reproduced PAO effects on both steroidogenesis and StAR protein. Taken together, these results indicate that PTP activity participates in StAR protein induction and led us to attribute to the PKA-mediated PTP activation in steroidogenic systems a functional role, as mediator of StAR protein induction.

In isolated human umbilical vein (HUV), the contractile response to des-Arg9-bradykinin (des-Arg9-BK), selective BK B1 receptor agonist, increases as a function of the incubation time. Here, we evaluated whether cyclooxygenase (COX) pathway is involved in BK B1-sensitized response obtained in 5-h incubated HUV rings. The effect of different concentrations of indomethacin, sodium salicylate, ibuprofen, meloxicam, lysine clonixinate or NS-398 administrated 30 min before concentration-response curves (CRC) was studied. All treatments produced a significant rightward shift of the CRC to des-Arg9-BK in a concentration-dependent manner, which provides pharmacological evidence that COX pathway is involved in the BK B1 responses. Moreover, in this tissue, the NS-398 pKb (5.2) observed suggests that COX-2 pathway is the most relevant. The strong correlation between published pIC50 for COX-2 and the NSAIDs' pKbs estimated further supports the hypothesis that COX-2 metabolites are involved in BK B1 receptor-mediated responses. In other rings, indomethacin (30, 100 micromol/l) or NS-398 (10, 30 micromol/l) produced a significant rightward shift of the CRC to BK, selective BK B2 agonist, and its pKbs were similar to the values to inhibit BK B1 receptor responses, suggesting that COX-2 pathway also is involved in BK B2 receptor responses. Western blot analysis shows that COX-1 and COX-2 isoenzymes are present before and after 5-h in vitro incubation and apparently COX-2 does not suffer additional induction.

Our recent reports indicate that protein tyrosine phosphorylation is an obligatory component of the mechanism of action of ACTH in its stimulatory action of corticosteroid production in adrenal zona fasciculata (ZF). The role of protein tyrosine phosphatase (PTP) activity in the regulation of steroidogenesis by LH/chorionic gonadotropin (CG) was tested using cell-permeable PTP inhibitors. Thus, PTP inhibition blocks LH- and 8-bromo-cAMP-stimulated testosterone production by Leydig cells without affecting 22(R)OH-cholesterol-supported steroidogenesis, similar results to those obtained in the adrenal ZF/ACTH system, leading us to propose that PTP action is an obligatory and common step in the cascade triggered by both hormones. Then, we continued the study testing whether LH modulates PTP activity in MA-10 cells, a Leydig cell line. In this regard, we observed by an in-gel PTP assay two PTPs of 110 and 50 kDa that are activated by hormone and 8-bromo-cAMP activation of the cells. Moreover, there is a transient increase by the second messenger in total PTP activity that correlates with the higher activity displayed by the 110 and 50 kDa proteins in the in-gel assay. In accordance with these results, analysis of tyrosine phosphorylated proteins showed the LH-induced dephosphorylation of proteins of 120, 68 and 50 kDa. The results of this study indicate that PTPs play an important role in the regulation of Leydig cell functions and that there exists a cross talk between serine/threonine phosphorylation and tyrosine dephosphorylation mediated by hormone-activated cAMP-dependent protein kinase and PTPs. These results are the first evidence of PTP having a role in LH/CG-stimulated steroidogenesis.

Telomeric association (TA), i.e. fusion of chromosomes by their telomeres, predisposes a cell to genetic instability. Because of this we investigated the effect of X-rays exposure and cigarette smoking on the frequency of TA in peripheral blood lymphocytes of exposed individuals, in order to determine if TA can be a chromosomal marker in populations exposed to these carcinogens and if there is an synergistic effect between both agents. We found that the exposed groups show a greater percentage of TA when compared with the control group (P<0.001). However, although the percentage of metaphases with TA in the group with combined exposure (12.6%) was greater than in the others exposed groups (P<0.05), this value was less than the sum of the two individual effects (15.1%). Our results suggest that probably there is not an additive or synergistic effect between X-rays and smoking, and that TA may be a useful cytogenetic marker for evaluating populations exposed to mutagens.

It has been well established that arachidonic acid (AA) and its metabolism to leukotrienes plays an obligatory role in steroid production. The release of AA is regulated by hormone stimulation and protein phosphorylation. We have cloned a cDNA of a phosphoprotein with a molecular mass of 43 kDa (p43), purified from the cytosol of stimulated adrenal glands. This protein acts as intermediary in the stimulation of steroid synthesis through AA release, and has been found to be a member of a recently described acyl-CoA thioesterase family. In view of the mandatory role of this protein in the activation of AA-mediated steroidogenesis, the term Arachidonic acid-Related Thioesterase Involved in Steroidogenesis (ARTISt), is proposed for p43. The present study describes the production of the recombinant protein by cDNA expression in Escherichia coli and its functional characterization. Recombinant acyl-CoA thioesterase was capable to release AA from the respective acyl-CoA, and this activity was affected by well-recognized inhibitors of AA release and metabolism: 4-bromophenacyl bromide (BPB) and nordihydroguariaretic acid (NDGA). In addition, the inhibition of acyl-CoA thioesterase activity by NDGA correlates with the inhibition of steroid synthesis produced by this compound in adrenal cortex cells. Moreover, the recombinant protein was phosphorylated in vitro by PKA. These results provide the first evidence linking acyl-CoA thioesterases with the regulation of steroidogenesis, and support a regulatory role for acyl-CoA thioesterases in steroidogenic tissues, suggesting an alternative pathway for AA release in signal transduction.

In adrenal cortex, ACTH regulation of steroidogenesis depends on PKA-dependent serine/threonine phosphorylation and also on the activity of protein tyrosine phosphatases (PTPs). In addition, ACTH increases total PTPs involving at least three soluble PTPs (50, 82 and 115 kDa). Serine/threonine phosphorylation of these enzymes themselves could be a regulatory mechanism of their activity since the increase of total PTP activity is dependent on PKA-activation. In this report we analyzed the effect of in vitro phospho-dephosphorylation processes on the activity displayed by the ACTH-activated PTP of 115 kDa. Using an in-gel PTP assay we demonstrate that dephosphorylation catalyzed by potato acid phosphatase (PAP) reduces the activity of the 115 kDa PTP present in ZF from ACTH-treated animals and PKA-mediated phosphorylation reverses this effect.

The present study analyzes the morphological aspects of the cerebellum of rats with prenatal exposure to ozone. A double blind histological and planimetric analysis was performed studying sagittal sections of the anterior cerebellar lobe at postnatal days 0, 12 and 60. Ozone exposed rats showed cerebellar necrotic signs at age 0, diminished area of the molecular layer with Purkinje cells with pale nucleoli and perinucleolar bodies at age 12, and Purkinje cells showing nuclei with unusual clumps of chromatin in the periphery at age 60. We conclude that exposure to high concentrations of ozone during gestation induces permanent cerebellar damage in rats.