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Using the Cauchy integral theorem, we develop the application of the steepest descent method to efficiently compute the three-dimensional acoustic single-layer integral operator for large wave numbers. Explicit formulas for the splitting points are derived in the one-dimensional case to build suitable complex integration paths. The construction of admissible steepest descent paths is next investigated and some of their properties are stated. Based on these theoretical results, we derive the quadrature scheme of the oscillatory integrals first in dimension one and then extend the methodology to three-dimensional planar triangles. Numerical simulations are finally reported to illustrate the accuracy and efficiency of the proposed approach.

VIII Conference on Mechanical Response of Composites : M. Fagerström & G. Catalanotti (Editors) 8th Conference on Mechanical Response of Composites, Composites 2021, online, 22 Sep 2021 - 24 Sep 2021; CIMNE 13 Seiten (2021). doi:10.23967/composites.2021.061, Published by CIMNE

Background: Itching is considered to be a subjective symptom of the activation of neurosensory structures by different signal molecules and trigger factors. The signaling cascades responsible for it are closely linked to inflammatory processes. This explains why itching also occurs in many inflammatory diseases. One of these signaling cascades is mediated by Janus kinases (JAKs). Recently, it could be shown on a molecular level that Janus kinase 1 (JAK1) directly activates frontal cortex neurons and thus can cause chronic itching. Objectives: This study deals with the influence of different JAK inhibitors (JAKi) on the activity of chip-based neural networks of cultured frontal cortex neurons by investigating neurophysiological activity parameters. This in vitro model provides information on dose-dependent effects of model substances with different specificity regarding the inhibition of different JAKs. Methods: Tofacitinib (pan-JAKi), baricitinib (JAK1/2i), and upadacitinib (JAK1i) in a concentration range from 10 nmol/L to 50 μmol/L were tested in a microelectrode array neurochip culture system. Results: The results show that the inhibition of the neuronal activity of frontal cortex neurons increases with JAK1 selectivity and is dependent on concentration. Conclusion: These observations are supported by data from clinical studies in atopic dermatitis and psoriasis. The clinical relevance of these results must be proven by further clinical studies with subjective and objective parameters for itching.

В последнее время обнаружено наличие сегнетоэлектрических свойств наноразмерных пленок на основе оксида гафния. Такие пленки представляют большой интерес для разработки универсальной памяти, которая сочетает преимущества оперативной и флэш-памяти. В работе изучаются оптические свойства пленок оксида гафния-циркония HfxZryO2 и пленок оксида гафния-циркония, легированных лантаном, La : HfxZryO2. Флуктуации толщины пленок HfxZryO2 не превышают 3.5%, флуктуации толщины пленок La : HfxZryO2 --- 3.2%. Оптические свойства анализируются на основе теории эффективной среды. По данным теории эффективной среды пленки HfxZryO2 содержат 46% HfO2, 54% ZrO2, пленки La : HfxZryO2 содержат 47.5% HfO2, 52.4% ZrO2, 2.5% La2O3. Ключевые слова: сегнетоэлектрик, показатель преломления, спектроэллипсометрия, теория эффективной среды.

Thin lm metal–insulator–metal capacitors with undoped HfO2 as the insulator are fabricated by sputtering from ceramic targets and subsequently annealed. The in uence of lm thickness and annealing temperature is characterized by electrical and structural methods. After annealing, the lms show distinct ferroelectric properties. Grazing incidence X-ray diffraction measurements reveal a dominant ferroelectric orthorhombic phase for thick- nesses in the 10–50 nm range and a negligible non-ferroelectric monoclinic phase fraction. Sputtering HfO2 with additional oxygen during the deposition decreases the remanent polarization. Overall, the impact of oxygen vacancies and interstitials in the HfO2 lm during deposition and annealing is correlated to the phase formation process., T.S., M.M., I.S., and M.C. received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 780302 (project 3εFerro). M.H.P. was supported by Humboldt postdoctoral fellowship from Alexander von Humboldt Foundation and later by the Basic Science Research Program through an NRF (National Research Foundation of Korea) grant funded by the Ministry of Education (NRF-2018R1C1B5086580). P.D.L was funded by the German Ministry of Economic Affairs and Energy (BMWi) project (16IPCEI310). This work was performed in part at the Analytical Instrumentation Facility (AIF) at North Carolina State Univ., which was supported by the State of North Carolina and the National Science Foundation (Award No. ECCS-1542015). The AIF is a member of the North Carolina Research Triangle Nanotechnology Network (RTNN), a site in the National Nanotechnology Coordinated Infrastructure (NNCI). The authors thank Ilya Karpov for helpful discussions on the topics of oxygen vacancies and phase stability. The authors also thank Robin Materlik and Christopher Künneth for providing their simulation data and fruitful discussions.

Brain development is likely impacted by micronutrients. This is supported by the effects of the ω-3 fatty acid docosahexaenoic acid (DHA) during early neuronal differentiation, when it increases neurite growth. Aiming to delineate DHA roles in postnatal stages, we selected the visual cortex due to its stereotypic maturation. Immunohistochemistry showed that young mice that received dietary DHA from birth exhibited more abundant presynaptic and postsynaptic specializations. DHA also increased density and size of synapses in a dose-dependent manner in cultured neurons. In addition, dendritic arbors of neurons treated with DHA were more complex. In agreement with improved connectivity, DHA enhanced physiological parameters of network maturation in vitro, including bursting strength and oscillatory behavior. Aiming to analyze functional maturation of the cortex, we performed in vivo electrophysiological recordings from awake mice to measure responses to patterned visual inputs. Dietary DHA robustly promoted the developmental increase in visual acuity, without altering light sensitivity. The visual acuity of DHA-supplemented animals continued to improve even after their cortex had matured and DHA abolished the acuity plateau. Our findings show that the ω-3 fatty acid DHA promotes synaptic connectivity and cortical processing. These results provide evidence that micronutrients can support the maturation of neuronal networks.

Background: Details of the extraction and purification procedure can have a profound impact on the composition of plant-derived extracts, and thus on their efficacy and safety. So far, studies with head-to-head comparison of the pharmacology of Ginkgo extracts rendered by different procedures have been rare. Objective: The objective of this study was to explore whether Ginkgo biloba L. (Ginkgoaceae) leaf extract medications of various sources protect against amyloid beta toxicity on primary mouse cortex neurons growing on microelectrode arrays, and whether the effects differ between different Ginkgo extracts. Design: Our brain-on-chip platform integrates microelectrode array data recorded on neuronal tissue cultures from embryonic mouse cortex. Amyloid beta 42 (Aβ42) and various Ginkgo extract preparations were added to the networks in vitro before evaluation of electrophysiological parameters by multi-parametric analysis. A Multi-variate data analysis, called Effect Score, was designed to compare effects between different products. Results: The results show that Ginkgo extracts protected against Aβ42-induced electrophysiological alterations. Different Ginkgo extracts exhibited different effects. Of note, the reference Ginkgo biloba L. (Ginkgoaceae) leaf medication Tebonin had the most pronounced rescuing effect. Conclusion: Here, we show for the first time a side-by-side analysis of a large number of Ginkgo medications in a relevant in vitro system modeling early functional effects induced by amyloid beta peptides on neuronal transmission and connectivity. Ginkgo biloba L. (Ginkgoaceae) leaf extract from different manufactures exhibit differential functional effects in this neural network model. This in-depth analysis of functional phenotypes of neurons cultured on MEAs chips allows identifying optimal plant extract formulations protecting against toxin-induced functional effects in vitro.

Die transorale Lasermikrochirurgie (TLM) ist die Methode der Wahl fur Larynxteilresektionen in Deutschland. In fortgeschrittenen Stadien wird zunehmend haufig die Radiochemotherapie zum Organerhalt indiziert. Die Indikation und Ergebnisse der suprakrikoidalen Larynxteilresektion (SPL), auch als Krikohyoido(epiglotto)pexie bekannt, soll als Option des chirurgischen Organerhalts beim moderat fortgeschrittenen Glottiskarzinom (T3–T4a) im Spannungsfeld zwischen TLM und Radiochemotherapieprotokollen in Deutschland dargestellt werden. Retrospektive Evaluation der funktionellen und onkologischen Ergebnisse aller SPL von 2008 bis 2014. Im genannten Zeitraum wurden 17 SPL mit Resektion eines Arytanoidknorpels im Stadium rpT2 (n = 2), (r)pT3 (n = 11) und (r)pT4a (n = 4) durchgefuhrt. Das mittlere Alter betrug 58, die Spanne 47–75 Jahre. Bei 5 Patienten bestand ein erstes oder zweites Rezidiv nach TLM oder offener Teilresektion. Sieben Patienten mit rpT4a oder pN+ wurden adjuvant bestrahlt. Zwei Patienten mussten sich einer Salvage-Laryngektomie mit adjuvanter Strahlentherapie unterziehen. Alle anderen Patienten (n = 15) zeigten eine im Mittel 4 Jahre lange tumorfreie Nachsorge mit funktionell intaktem Larynx: Sie ernahren sich peroral, haben ein verschlossenes Tracheostoma und eine gute Sprache. Zwei Patienten starben mit 76 Jahren nach 3 Jahren tumorfreier Nachsorge mit funktionell intaktem Larynx. Die SPL ist beim Larynxkarzinom pT3–4a eine seltene, aber wertvolle Option des chirurgischen Larynxerhalts.

In the present study, we have elucidated the functional characteristics and mechanism of action of methaqualone (2-methyl-3-o-tolyl-4(3H)-quinazolinone, Quaalude), an infamous sedative-hypnotic and recreational drug from the 1960s-1970s. Methaqualone was demonstrated to be a positive allosteric modulator at human α1,2,3,5β2,3γ2S GABAA receptors (GABAARs) expressed in Xenopus oocytes, whereas it displayed highly diverse functionalities at the α4,6β1,2,3δ GABAAR subtypes, ranging from inactivity (α4β1δ), through negative (α6β1δ) or positive allosteric modulation (α4β2δ, α6β2,3δ), to superagonism (α4β3δ). Methaqualone did not interact with the benzodiazepine, barbiturate, or neurosteroid binding sites in the GABAAR. Instead, the compound is proposed to act through the transmembrane β((+))/α((-)) subunit interface of the receptor, possibly targeting a site overlapping with that of the general anesthetic etomidate. The negligible activities displayed by methaqualone at numerous neurotransmitter receptors and transporters in an elaborate screening for additional putative central nervous system (CNS) targets suggest that it is a selective GABAAR modulator. The mode of action of methaqualone was further investigated in multichannel recordings from primary frontal cortex networks, where the overall activity changes induced by the compound at 1-100 μM concentrations were quite similar to those mediated by other CNS depressants. Finally, the free methaqualone concentrations in the mouse brain arising from doses producing significant in vivo effects in assays for locomotion and anticonvulsant activity correlated fairly well with its potencies as a modulator at the recombinant GABAARs. Hence, we propose that the multifaceted functional properties exhibited by methaqualone at GABAARs give rise to its effects as a therapeutic and recreational drug.

Background The German multicenter randomized phase II larynx organ preservation (LOP) trial DeLOS-II was carried out to prove the hypothesis that cetuximab (E) added to induction chemotherapy (IC) and radiotherapy improves laryngectomy-free survival (LFS; survival with preserved larynx) in locally advanced laryngeal/hypopharyngeal cancer (LHSCC). Patients and methods Treatment-naive patients with stage III/IV LHSCC amenable to total laryngectomy (TL) were randomized to three cycles IC with TPF [docetaxel (T) and cisplatin (P) 75 mg/m2/day 1, 5-FU (F) 750 mg/m2/day days 1–5] followed by radiotherapy (69.6 Gy) without (A) or with (B) standard dose cetuximab for 16 weeks throughout IC and radiotherapy (TPFE). Response to first IC-cycle (IC-1) with ≥30% endoscopically estimated tumor surface shrinkage (ETSS) was used to define early responders; early salvage TL was recommended to non-responders. The primary objective was 24 months LFS above 35% in arm B. Results Of 180 patients randomized (July 2007 to September 2012), 173 fulfilled eligibility criteria (A/B: larynx 44/42, hypopharynx 41/46). Because of 4 therapy-related deaths among the first 64 randomized patients, 5-FU was omitted from IC in the subsequent 112 patients reducing further fatal toxicities. Thus, IC was TPF in 61 patients and TP in 112 patients, respectively. The primary objective (24 months LFS above 35%) was equally met by arms A (40/85, 47.1%) as well as B (41/88, 46.6%). One hundred and twenty-three early responders completed IC+RT; their overall response rates (TPF/TP) were 94.7%/87.2% in A versus 80%/86.0% in B. The 24 months overall survival (OS) rates were 68.2% and 69.3%. Conclusions Despite being accompanied by an elevated frequency in adverse events, the IC with TPF/TP plus cetuximab was feasible but showed no superiority to IC with TPF/TP regarding LFS and OS at 24 months. Both early response and 24 months LFS compare very well to previous LOP trials and recommend effective treatment selection and stratification by ETSS. Clinical trial information NCT00508664.

The therapy of complicated Kaposiform hemangioendothelioma (KHE) is still difficult. We present the first case of laryngomalacia with simultaneous mammalian target of Rapamycin (mTOR)-positive KHE of the neck and thoracic inlet and concurrent Kasabach-Meritt Phenomenon (KMP) in an 11-month-old boy suffering life-threatening progress despite intravenous vincristine, corticosteroids, propranolol and local interstitial laser-application. The laryngomalacia restored after laser-supraglottoplasty. Successfully treatment of the prior fatal course of the KHE with KMP was initiated not till adding the mTOR inhibitor sirolimus to therapy. After 16 months single therapy of KHE with oral sirolimus the boy presented free of symptoms with minimal residual disease and excellent functional long-term results. Thus we stopped sirolimus therapy. The results are stable for 9 months without therapy. The special features including full report of histopathologic findings of this utmost complicated case are demonstrated in detail underlining the effectiveness of sirolimus for KHE.

In head and neck squamous cell carcinoma (HNSCC) aerobic glycolysis is the key feature for energy supply of the tumor. Quantitative microdialysis (μD) offers an online method to measure parameters of the carbohydrate metabolism in vivo. The aim was to standardize a quantitative μD-study in patients with HNSCC and to prove if a ketogenic diet would differently influence the carbohydrate metabolism of the tumor tissue. Commercially available 100 kDa-CMA71-μD- catheters were implanted in tumor-free and in tumor tissue in patients with HNSCC for simultaneous measurements up to 5 days. The metabolic pattern and circadian rhythm of urea, glucose, lactate, and pyruvate was monitored during 24 h of western diet and subsequent up to 4 days of ketogenic diet. After 3 days of ketogenic diet the mean lactate concentration declines to a greater extent in the tumor tissue than in the tumor-free mucosa, whereas the mean glucose and pyruvate concentrations rise. The in vivo glucose metabolism of the tumor tissue is clearly influenced by nutrition. The decline of mean lactate concentration in the tumor tissue after ketogenic diet supports the hypothesis that HNSCC tumor cells might use lactate as fuel for oxidative glucose metabolism.

Microelectrode arrays (MEAs) have been in use over the past decade and a half to study multiple aspects of electrically excitable cells. In particular, MEAs have been applied to explore the pharmacological and toxicological effects of numerous compounds on spontaneous activity of neuronal and cardiac cell networks. The MEA system enables simultaneous extracellular recordings from multiple sites in the network in real time, increasing spatial resolution and thereby providing a robust measure of network activity. The simultaneous gathering of action potential and field potential data over long periods of time allows the monitoring of network functions that arise from the interaction of all cellular mechanisms responsible for spatio-temporal pattern generation. In these functional, dynamic systems, physical, chemical, and pharmacological perturbations are holistically reflected by the tissue responses. Such features make MEA technology well suited for the screening of compounds of interest, and also allow scaling to high throughput systems that can record from multiple, separate cell networks simultaneously in multi-well chips or plates. This article is designed to be useful to newcomers to this technology as well as those who are currently using MEAs in their research. It explains how MEA systems operate, summarizes what systems are available, and provides a discussion of emerging mathematical schemes that can be used for a rapid classification of drug or chemical effects. Current efforts that will expand this technology to an influential, high throughput, electrophysiological approach for reliable determinations of compound toxicity are also described and a comprehensive review of toxicological publications using MEAs is provided as an appendix to this publication. Overall, this article highlights the benefits and promise of MEA technology as a high throughput, rapid screening method for toxicity testing.

De-excitation modes of compound systems 118Ba and 134Ba, produced respectively in the 78Kr+40Ca and 86Kr+48Ca collisions at 10 A.MeV, are investigated. In particular, the competition between the various disintegration decay paths of medium mass compound nuclei, formed by fusion processes and the isospin (related to N/Z) of the entrance channel influence on the decay process, are studied. Data were taken at the INFN-Laboratori Nazionali del Sud (LNS) in ISODEC experiment, by using the CHIMERA array. The experiment complements and improves the previous experiment performed at GANIL where the same mechanisms were studied at lower excitation energies. The results show the presence of a relaxed component in the reaction mechanism, evident staggering effects in the Z distributions, as well as different isotopic composition and neutron enrichment for the reaction products in the two systems.

Expérience GANIL; International audience; Decay modes of excited compound systems 118Ba and 134Ba, produced respectively in the 78Kr+40Ca and 86Kr+48Ca collisions at 10 A*MeV, are investigated. In particular, the competition between the various disintegration path of medium mass compound nuclei, formed by fusion processes, the production of the so referred Intermediate Mass Fragments (IMF), and the isospin dependence of the decay process are studied. Data were taken at the INFN-Laboratori Nazionali del Sud (LNS) by using the CHIMERA array. Data analysis is in progress; a first indication on the average-energy angular distributions suggests pre-equilibrium effects affecting the data and the presence of isotopical effects.

International audience; The study of the decay modes competition of the compound systems produced in thecollisions 78Kr+40Ca and 86Kr+48Ca at 10AMeV is presented. In particular, the N/Z entrance channelinfluence on the decay paths of the compound systems, directly connected to the isospin influence, isinvestigated. The experiment was performed at the INFN Laboratori Nazionali del Sud (LNS) inCatania by using the 4π multi-detector CHIMERA. Charge, mass, angular distributions andkinematical features of the reaction products were studied. The analysis shows some differences in thecontribution arising from the various reaction mechanisms for the neutron poor and neutron richsystems. Comparison with theoretical statistical and dynamical models are presented for the twosystems. Besides a study of the influence of the energy on the entrance channel is performed for the78Kr+40Ca reaction, by comparing the results of this experiment to those obtained for the same systemat 5.5 AMeV with the INDRA device at GANIL.

Transoral laser microsurgery (TLM) is the method of choice for partial laryngectomy in Germany. In advanced stages, chemoradiotherapy is increasingly indicated for organ preservation.This report considers the indications for and outcomes of supracricoid partial laryngectomy (SPL), also known as crico-hyoido-(epiglotto)-pexy, as an option for surgical organ preservation in moderately advanced laryngeal cancer (T3-T4a), in the well-defined gap between TLM and chemoradiotherapy protocols in Germany.Retrospective evaluation of functional and oncological outcomes of all SPLs conducted between 2008 and 2014. During this period, 17 SPLs with resection of rpT2 (n = 2), (r)pT3 (n = 11), and (r)pT4a (n = 4) were performed with resection of one arytenoid. Mean age was 58 years (range 47-75 years). In 5 patients, SPL was for a first or second local recurrence after TLM or open partial laryngectomy. Adjuvant radiotherapy was received by 7 patients staged pT4a or pN+.Salvage laryngectomy with adjuvant radiotherapy was required by 2 patients. The remaining patients (n = 15) had a mean tumor-free follow-up of 4 years with a functional intact larynx: these patients can eat and drink, have a closed tracheotomy, and a good voice. After 3 years tumor-free follow-up with a functional intact larynx, 2 patients died due to cardiac comorbidity at the age of 76 years.SPL is a rare but valuable option for surgical larynx preservation in stage pT3-4a laryngeal cancer.

We present a possible design of future large-scale dark matter detector using liquid xenon. A low energy threshold is achieved by using a large CsI-coated internal photocathode for primary light collection. A focusing field, in the active volume and an electron focusing structure at the liquid surface, are used to transport free-electrons to the luminescence field. A 3D reconstruction of the events can be achieved by timing and location of the luminescent signal. A liquid xenon Compton veto and self-shield are integrated in the compact design. This detector could be used to probe most of the SUSY predicted dark matter. ZEPLIN IV can be initially tested at Boulby and then be moved to the USA to operate at a US deep underground science and engineering laboratory.

ZEPLIN II is a 30-kg two-phase xenon detector designed for direct detection of cold dark matter in the form of WIMPs. Currently in the commissioning phase, it will begin operation in the Boulby Mine, UK later this year. ZEPLIN II is capable of discriminating between nuclear recoils and background events and has a design reach up to two orders of magnitude beyond current limits. It will also serve as a step in the development program for a next-generation ton-scale detector.

International audience; Preliminary outcome of ISODEC experiment, performed at INFNLNS with the CHIMERA array, are presented. Disintegration path dependence on the entrance-channel N/Z ratios (isospin asymmetries) for the reactions 78Kr+40Ca and 86Kr+48Ca at 10 A*MeV, which give origin to the intermediate systems 118Ba and 134Ba, is being investigated. Staggering effects seem to be present as it was the case of a complementary measurement performed at GANIL at lower energy, i.e. 78,82Kr+40Ca at 5.5 A*MeV.

International audience; We present the first results of the ISODEC experiment, performed at the INFN-LNS with the CHIMERA device, in order to study the competition between the various disintegration modes of 118,134Ba compound nuclei produced by bombarding 40,48Ca targets with beams of 78,86Kr at 10 AMeV. This work aims thus to explore the isospin dependence of the decay modes of medium mass compound nuclei formed by fusion processes. The experiment complements data already obtained at 5.5 MeV/A for 78,82Kr+40Ca reactions, studied by Ademard et al. with beams delivered by GANIL facility and by using the INDRA detector.

Objective: To develop a short instrument to examine quality of life (QoL) which specifically addresses patients with movement disorders treated by deep brain stimulation (DBS). Design: The instrument was developed within an existing concept of a modular questionnaire (questions on life satisfaction: “general life satisfaction” QLS M -A, and “satisfaction with health” QLS M -G), in which each item is weighted according to its relative importance to the individual. Methods: Items were generated by interviews with 20 DBS patients, followed by item reduction and scale generation, factor analysis to determine relevant and final questionnaire items, estimation of reliability, and validation based on the medical outcome study 36 item short form health survey (SF-36) and the EuroQol (EQ-5D) (data from 152 patients with Parkinson’s disease, essential tremor, or idiopathic torsion dystonia, including 75 patients with DBS). Results: Initial questionnaires were reduced to 12 items for a “movement disorder module” (QLS M -MD), and five items for a “deep brain stimulation module” (QLS M -DBS). Psychometric analysis revealed Cronbach’s α values of of 0.87 and 0.73, and satisfactory correlation coefficients for convergent validity with SF-36 and EQ-5D. Conclusions: QLS M -MD and QLS M -DBS can evaluate quality of life aspects of DBS in movement disorders. Psychometric evaluation showed the questionnaires to be reliable, valid, and well accepted by the patients.

Obwohl die Glottis im Grunde zur Chemopravention pradisponiert ist, werden derzeit nahezu alle laryngealen Dysplasien von Stadium I bis hin zum Carcinoma in situ exzidiert. In der Ubersicht werden einige ausgewahlte molekularbiologische Aspekte mit besonderer Beziehung zur Dysplasie des Larynx und therapeutischer Relevanz vorgestellt und aktuell favorisierte Biomarker zur Chemopravention laryngealer Dysplasien diskutiert.

The subthalamic nucleus (STN) has generally been considered as a relay station within frontal-subcortical motor control circuitry. Little is known about the influence of the STN on cognitive networks. Clinical observations and studies in animals suggest that the STN participates in non-motor functions which can now be probed in Parkinson's disease patients with deep brain stimulation of the STN, allowing selective and reversible modulation of this nucleus. Using PET, we studied changes in regional cerebral blood flow (rCBF) associated with a response conflict task (Stroop task) in Parkinson's disease patients ON and OFF bilateral STN stimulation. The Stroop task requires subjects to name the font colour of colour words (e.g. "blue") printed in an incongruent colour ink (e.g. yellow). During STN stimulation, impaired task performance (prolonged reaction times) was associated with decreased activation in both right anterior cingulate cortex (ACC) and right ventral striatum. Concomitant increased activation in left angular gyrus indicative of ongoing word processing during stimulation is consistent with an impairment to inhibit habitual responses. ACC and ventral striatum are part of the ACC circuit associated with response conflict tasks. The decreased activation during STN stimulation in the ACC circuit, while response conflict processing worsened, provides direct evidence of STN modulating non-motor basal ganglia-thalamocortical circuitry. Impairment in ACC circuit function could account for the subtle negative effects on cognition induced by STN stimulation.

The electrical characteristics of layered Al2O3 /Pr2O3/Al2O3 metal-insulator-metal (MIM) capacitors for RF device applications are presented for the first time. This advanced dielectric layer system 4-nm Al2O3/8-nm Pr2O3/4-nm Al2O3 shows a high capacitance density of 5.7 fF/mum2, a low leakage current density of 5times10-9 A/cm2 at 1 V, and an excellent dielectric loss behavior over the studied frequency range

In this paper, we have presented the need for Middle of Line (MOL) Local Interconnects in a fixed layout shape called “Special Constructs” in order to make 20nm a very compelling technology for product migration from 28nm. These constructs are used to demonstrate considerable area, cost, and power/performance benefits by enabling efficient and manufacturable high density standard cell libraries. Also, these constructs have become an essential elements of optical lithography based advanced CMOS nodes for cost effective technology scaling even beyond 20nm.

This paper discusses concepts missing from the World Wide Web, hindering its service as an appropriate teaching and learning environment. An approach for computer-based training systems which are not based on the WWW is introduced.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor signs in Parkinson’s disease. However, clinical studies suggest that DBS of the STN may also affect cognitive and emotional functions. Objective: To study the impact of STN stimulation in Parkinson’s disease on perception of facial expressions. Results: There was a selective reduction in recognition of angry faces, but not other expressions, during STN stimulation. Conclusions: The findings may have important implications for social adjustment in these patients.

The de-excitation of medium mass nuclei 118,134Ba produced in fusion process of 78,86Kr on 40,48Ca targets at 10 AMeV is studied, in order to investigate the isospin dependence of the decay modes; the neutron enrichment of the compound nuclei is in fact expected to play an important role on the emission mechanisms, providing crucial information on fundamental nuclear quantities such as level density, fission barrier, viscosity and symmetry energy. The experiment was performed at INFN-LNS with the 4π multidetector for charged particles CHIMERA, used for the first time in this low energy regime, thanks to a suitable Pulse Shape Discrimination method for charge identification applied to the silicon detectors. Preliminary results show a different isotopic composition and relative enrichment for the same Z in the two systems. The yields of the Intermediate Mass Fragments (IMF, 3

Persistent pain states, such as those caused by nerve injury or inflammation, are associated with altered sensations, allodynia and hyperalgesia, that are resistant to traditional analgesics. A contribution to development and maintenance in altered pain perception comes from nociceptive processing and descending modulation from supraspinal sites. A multitarget ligand seems to be useful for pain relief with a decreased risk of adverse events and a considerable analgesic efficacy. The multitarget MOR agonist-DOR antagonist LP1, (3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benazocin-3(2H)-yl]-N-phenylpropanamide, is a central acting antinociceptive agent with low potential to induce tolerance. LP1 was tested in models of neuropathic pain - induced by chronic constriction injury (CCI) of the left sciatic nerve - and inflammatory pain - produced by intraplantar injection of carrageenan. In CCI rats, subcutaneous (s.c.) LP1 (3 mg/kg) showed a significant antiallodynic effect, measured with von Frey filaments, and antihyperalgesic effect, evoked in response to a radiant heat stimulus with plantar test. Analogously, LP1 significantly reduced allodynic and hyperalgesic thresholds in a model of inflammatory pain induced by carrageenan. To evaluate the contribution of opioid receptor subtypes in LP1 antinociceptive effects, the multitarget LP1 profile was assessed using selective opioid antagonists. Moreover, functional electrophysiological in vitro assays, using primary cortical and spinal cord networks, allowed to define the "pharmacological fingerprint" of LP1. The EC₅₀ values in this functional screening seem to confirm LP1 as a potent opioid ligand (EC₅₀ = 0.35 fM and EC₅₀ = 44 pM in spinal cord and frontal cortex, respectively). Using a NeuroProof data-base of well characterised reference compounds, a similarity profile of LP1 to opioid and non-opioid drugs involved in pain modulation was detected. Our studies seem to support that multitarget ligand approach should be useful for persistent pain conditions in which mechanical allodynia and thermal hyperalgesia are significant components of the nociceptive response.

Although the glottis is amenable to chemotherapy, currently most lesions from stage I laryngeal dysplasia up to carcinoma in situ are excised. This literature review presents selected molecular biological aspects especially in relation to dysplasia of the larynx and its therapy, as well as currently preferred biomarkers for chemotherapeutic prevention of laryngeal dysplasia.

Industry's extensive knowledge of fabricating bulk CMOS planar transistors has made them the device of choice for the cost sensitive foundry semiconductor sector. On advanced nodes the scaling benefits for SoCs will be based on a set of Key Performance Indicators (KPIs) (Fig.1) quantified by measurable Figures of Merit (FOMs). These KPIs cover a range of requirements from system level performance, power, and die area scaling to manufacturing cost, production risk, reliability limitations, designabilty and technology extension for a broad domain of SoCs. Critical performance FOMs include Fmax, compute density performance at constant power density (MHz/mW/mm2) and performance vs. power for a given cost (PPC) (MHz/mW/$). The idea is to integrate the transistor and physical scaling benefits to offer a cost sensitive technology platform that provides value for the SoC applications and effectively for the end users. Fig. 1 illustrates the complexity of achieving this task to minimize the risk and TTV/TTM while addressing the difficult technical barriers. Device and circuit co-optimization enhances the SoC values measured by PPC, PPA, and Fmax.

Neuronal assemblies within the nervous system produce electrical activity that can be recorded in terms of action potential patterns. Such patterns provide a sensitive endpoint to detect effects of a variety of chemical and physical perturbations. They are a function of synaptic changes and do not necessarily involve structural alterations. In vitro neuronal networks (NNs) grown on Micro-Electrode Arrays (MEAs) respond to neuroactive substances as well as the in vivo brain. As such, they constitute a valuable tool for investigating changes in the electrophysiological activity of the neurons in response to chemical exposures. However, the reproducibility of NN responses to chemical exposure has not been systematically documented. To this purpose six independent laboratories (in Europe and in USA) evaluated the response to the same pharmacological compounds (Fluoxetine, Muscimol, and Verapamil) in primary neuronal cultures. Common standardization principles and acceptance criteria for the quality of the cultures have been established to compare the obtained results. These studies involved more than 100 experiments before the final conclusions have been drawn that MEA technology has a potential for standard in vitro neurotoxicity/neuropharmacology evaluation. The obtained results show good intra- and inter-laboratory reproducibility of the responses. The consistent inhibitory effects of the compounds were observed in all the laboratories with the 50% Inhibiting Concentrations (IC50s) ranging from: (mean ± S.E.M., in µM) 1.53±0.17 to 5.4±0.7 (n=35) for Fluoxetine, 0.16±0.03 to 0.38±0.16 µM (n=35) for Muscimol, and 2.68±0.32 to 5.23±1.7 (n=32) for Verapamil. The outcome of this study indicates that the MEA approach is a robust tool leading to reproducible results. The future direction will be to extend the set of testing compounds and to propose the MEA approach as a standard screen for identification and prioritization of chemicals with neurotoxicity potential., JRC.I.6-Systems toxicology