Characterization of cold sensitivity and thermal preference using an operant orofacial assay

BACKGROUND: A hallmark of many orofacial pain disorders is cold sensitivity, but relative to heat-related pain, mechanisms of cold perception and the development of cold allodynia are not clearly understood. Molecular mediators of cold sensation such as TRPM8 have been recently identified and characterized using in vitro studies. In this study we characterized operant behavior with respect to individually presented cold stimuli (24, 10, 2, and -4°C) and in a thermal preference task where rats chose between -4 and 48°C stimulation. We also evaluated the effects of menthol, a TRPM8 agonist, on operant responses to cold stimulation (24, 10, and -4°C). Male and female rats were trained to drink sweetened milk while pressing their shaved faces against a thermode. This presents a conflict paradigm between milk reward and thermal stimulation. RESULTS: We demonstrated that the cold stimulus response function was modest compared to heat. There was a significant effect of temperature on facial (stimulus) contacts, the ratio of licking contacts to stimulus contacts, and the stimulus duration/contact ratio. Males and females differed only in their facial contacts at 10°C. In the preference task, males preferred 48°C to -4°C, despite the fact that 48°C and -4°C were equally painful as based on their reward/stimulus and duration/contact ratios. We were able to induce hypersensitivity to cold using menthol at 10°C, but not at 24 or -4°C. CONCLUSION: Our results indicate a strong role for an affective component in processing of cold stimuli, more so than for heat, which is in concordance with human psychophysical findings. The induction of allodynia with menthol provides a model for cold allodynia. This study provides the basis for future studies involving orofacial pain and analgesics, and is translatable to the human experience

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

How can humans understand their automated cars? HMI principles, problems and solutions

As long as vehicles do not provide full automation, the design and function of the Human Machine Interface (HMI) is crucial for ensuring that the human “driver” and the vehicle-based automated systems collaborate in a safe manner. When the driver is decoupled from active control, the design of the HMI becomes even more critical. Without mutual understanding, the two agents (human and vehicle) will fail to accurately comprehend each other’s intentions and actions. This paper proposes a set of design principles for in-vehicle HMI and reviews some current HMI designs in the light of those principles. We argue that in many respects, the current designs fall short of best practice and have the potential to confuse the driver. This can lead to a mismatch between the operation of the automation in the light of the current external situation and the driver’s awareness of how well the automation is currently handling that situation. A model to illustrate how the various principles are interrelated is proposed. Finally, recommendations are made on how, building on each principle, HMI design solutions can be adopted to address these challenges

Optimised chronic infection models demonstrate that siderophore ‘cheating’ in Pseudomonas aeruginosa is context specific

The potential for siderophore mutants of Pseudomonas aeruginosa to attenuate virulence during infection, and the possibility of exploiting this for clinical ends, have attracted much discussion. This has largely been based on the results of in vitro experiments conducted in iron-limited growth medium, in which siderophore mutants act as social ‘cheats:’ increasing in frequency at the expense of the wild type to result in low-productivity, low-virulence populations dominated by mutants. We show that insights from in vitro experiments cannot necessarily be transferred to infection contexts. First, most published experiments use an undefined siderophore mutant. Whole-genome sequencing of this strain revealed a range of mutations affecting phenotypes other than siderophore production. Second, iron-limited medium provides a very different environment from that encountered in chronic infections. We conducted cheating assays using defined siderophore deletion mutants, in conditions designed to model infected fluids and tissue in cystic fibrosis lung infection and non-healing wounds. Depending on the environment, siderophore loss led to cheating, simple fitness defects, or no fitness effect at all. Our results show that it is crucial to develop defined in vitro models in order to predict whether siderophores are social, cheatable and suitable for clinical exploitation in specific infection contexts

A distinct role for B1b lymphocytes in T cell-independent immunity

Pathogenesis of infectious disease is not only determined by the virulence of the microbe but also by the immune status of the host. Vaccination is the most effective means to control infectious diseases. A hallmark of the adaptive immune system is the generation of B cell memory, which provides a long-lasting protective antibody response that is central to the concept of vaccination. Recent studies revealed a distinct function for B1b lymphocytes, a minor subset of mature B cells that closely resembles that of memory B cells in a number of aspects. In contrast to the development of conventional B cell memory, which requires the formation of germinal centers and T cells, the development of B1b cell-mediated long-lasting antibody responses occurs independent of T cell help. T cell-independent (TI) antigens are important virulence factors expressed by a number of bacterial pathogens, including those associated with biological threats. TI antigens cannot be processed and presented to T cells and therefore are known to possess restricted T cell-dependent (TD) immunogenicity. Nevertheless, specific recognition of TI antigens by B1b cells and the highly protective antibody responses mounted by them clearly indicate a crucial role for this subset of B cells. Understanding the mechanisms of long-term immunity conferred by B1b cells may lead to improved vaccine efficacy for a variety of TI antigens

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy. European Society of Human Genetics and European Society of Human Reproduction and Embryology.

In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation - ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide an update of selected topics that have evolved since 2005

Measurement of quarkonium production in proton–lead and proton–proton collisions at 5.02 TeV with the ATLAS detector

The modification of the production of J/ψ, ψ(2S), and Υ(nS) (n=1,2,3) in p+Pb collisions with respect to their production in pp collisions has been studied. The p+Pb and pp datasets used in this paper correspond to integrated luminosities of 28 nb−1 and 25 pb−1 respectively, collected in 2013 and 2015 by the ATLAS detector at the LHC, both at a centre-of-mass energy per nucleon pair of 5.02 TeV. The quarkonium states are reconstructed in the dimuon decay channel. The yields of J/ψ and ψ(2S) are separated into prompt and non-prompt sources. The measured quarkonium differential cross sections are presented as a function of rapidity and transverse momentum, as is the nuclear modification factor, RpPb for J/ψ and Υ(nS). No significant modification of the J/ψ production is observed while Υ(nS) production is found to be suppressed at low transverse momentum in p+Pb collisions relative to pp collisions. The production of excited charmonium and bottomonium states is found to be suppressed relative to that of the ground states in central p+Pb collisions

Manganese(II) Complexes with Schiff Bases Immobilized on Nanosilica as Catalysts of the Reaction of Ozone Decomposition

In this article, we submit the description of synthesis and identification of manganese(II) complexes with pyrogenic nanosilica-immobilized (d av = 10 nm; S sp = 290 m2/g) hydroxyaldimine ligands (Mn(L)2/Si): salicilaldiminopropyl (L1); 5-bromosalicilaldiminopropyl (L2); 2-hydroxynaphtaldiminopropyl (L3); 2-hydroxy-3-methoxybenzaldiminopropyl (L4); 2-hydroxy-3,5-dichloroacetophenoniminopropyl (L5); and 4-hydroxy-3-methoxybenzaldiminopropyl (L6). The ligands and complexes were characterized by UV-VIS and IR spectrometry. Nanocomposites consisting of complexes Mn(L)2/Si showed a high catalytic activity in low-temperature ozone decomposition in the range of concentrations between 2.1 × 10−6 and 8.4 × 10−6 mol/l. The number of catalytic cycles increased for isostructural pseudotetrahedral complexes Mn(L)2/Si (L1–L5) in the following order: Mn(L3)2 >> Mn(L4)2 > Mn(L1)2 > Mn(L2)2 > Mn(L5)2. In the case of pseudooctahedral complexes with L6, the change of coordination polyhedral does not influence the kinetics and stoichiometric parameters of the reaction

Radiographic and visual response to the type II RAF inhibitor tovorafenib in children with relapsed/ refractory optic pathway glioma in the FIREFLY-1 trial

\ua9 The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.Background. Due to their anatomical locations, optic pathway gliomas (OPGs) can rarely be cured by resection. Given the importance of preserving visual function, we analyzed radiological and visual acuity (VA) outcomes for the type II RAF inhibitor tovorafenib in the OPG subgroup of the phase 2 FIREFLY-1 trial. Methods. FIREFLY-1 investigated the efficacy (arm 1, n = 77), safety, and tolerability (arms 1/2) of tovorafenib (420 mg/m2 once weekly; 600 mg maximum) in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG). In this post hoc analysis, anti-tumor activity and VA were analyzed in arm 1 patients with OPG. Anti-tumor activity was independently assessed per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG), Response Assessment in Pediatric Neuro-Oncology-LGG (RAPNO), and RANO-LGG criteria.The data cutoff was June 5, 2023. Results. Forty-two of 77 patients had OPGs; 35 of 42 had ≥2 VA assessments.The overall response rate in the OPG subgroup according to RANO-HGG, RAPNO, and RANO-LGG criteria were 64%, 50%, and 55%, with clinical benefit rates of 95%, 88%, and 90%, respectively. VA per patient was preserved for 80% of patients; 31% demonstrated improved VA; VA per eye was preserved in 87%, with 27% improving.The safety profile in the arm 1 OPG subgroup was similar to the overall FIREFLY-1 safety analysis set. Conclusions. Tovorafenib demonstrated anti-tumor activity in relapsed/refractory BRAF-altered OPG across radiological assessment criteria and was generally well tolerated. Importantly, vision remained stable or improved in most patients