The thalamic low-threshold Ca2+ potential: a key determinant of the local and global dynamics of the slow (<1 Hz) sleep oscillation in thalamocortical networks

During non-rapid eye movement sleep and certain types of anaesthesia, neurons in the neocortex and thalamus exhibit a distinctive slow (<1 Hz) oscillation that consists of alternating UP and DOWN membrane potential states and which correlates with a pronounced slow (<1 Hz) rhythm in the electroencephalogram. While several studies have claimed that the slow oscillation is generated exclusively in neocortical networks and then transmitted to other brain areas, substantial evidence exists to suggest that the full expression of the slow oscillation in an intact thalamocortical (TC) network requires the balanced interaction of oscillator systems in both the neocortex and thalamus. Within such a scenario, we have previously argued that the powerful low-threshold Ca2+ potential (LTCP)-mediated burst of action potentials that initiates the UP states in individual TC neurons may be a vital signal for instigating UP states in related cortical areas. To investigate these issues we constructed a computational model of the TC network which encompasses the important known aspects of the slow oscillation that have been garnered from earlier in vivo and in vitro experiments. Using this model we confirm that the overall expression of the slow oscillation is intricately reliant on intact connections between the thalamus and the cortex. In particular, we demonstrate that UP state-related LTCP-mediated bursts in TC neurons are proficient in triggering synchronous UP states in cortical networks, thereby bringing about a synchronous slow oscillation in the whole network. The importance of LTCP-mediated action potential bursts in the slow oscillation is also underlined by the observation that their associated dendritic Ca2+ signals are the only ones that inform corticothalamic synapses of the TC neuron output, since they, but not those elicited by tonic action potential firing, reach the distal dendritic sites where these synapses are located

Optogenetic Recruitment of Dorsal Raphe Serotonergic Neurons Acutely Decreases Mechanosensory Responsivity in Behaving Mice

The inhibition of sensory responsivity is considered a core serotonin function, yet this hypothesis lacks direct support due to methodological obstacles. We adapted an optogenetic approach to induce acute, robust and specific firing of dorsal raphe serotonergic neurons. In vitro, the responsiveness of individual dorsal raphe serotonergic neurons to trains of light pulses varied with frequency and intensity as well as between cells, and the photostimulation protocol was therefore adjusted to maximize their overall output rate. In vivo, the photoactivation of dorsal raphe serotonergic neurons gave rise to a prominent light-evoked field response that displayed some sensitivity to a 5-HT1A agonist, consistent with autoreceptor inhibition of raphe neurons. In behaving mice, the photostimulation of dorsal raphe serotonergic neurons produced a rapid and reversible decrease in the animals' responses to plantar stimulation, providing a new level of evidence that serotonin gates sensory-driven responses.ERC 250334, 5-HT OptogeneticMSCA 220098info:eu-repo/semantics/publishedVersio

Trapped electron coupled to superconducting devices

We propose to couple a trapped single electron to superconducting structures located at a variable distance from the electron. The electron is captured in a cryogenic Penning trap using electric fields and a static magnetic field in the Tesla range. Measurements on the electron will allow investigating the properties of the superconductor such as vortex structure, damping and decoherence. We propose to couple a superconducting microwave resonator to the electron in order to realize a circuit QED-like experiment, as well as to couple superconducting Josephson junctions or superconducting quantum interferometers (SQUIDs) to the electron. The electron may also be coupled to a vortex which is situated in a double well potential, realized by nearby pinning centers in the superconductor, acting as a quantum mechanical two level system that can be controlled by a transport current tilting the double well potential. When the vortex is trapped in the interferometer arms of a SQUID, this would allow its detection both by the SQUID and by the electron.Comment: 13 pages, 5 figure

Barriers to HPV self-sampling and cytology among low-income indigenous women in rural areas of a middle-income setting: a qualitative study.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.BACKGROUND: Data is needed about barriers to self-collection of Human Papillomavirus (HPV) samples and cytology among low-income, disadvantaged women living in rural areas of lower-income countries as these women are at increased risk of cervical cancer mortality. METHODS: Individual interviews (n = 29), focus groups (n = 7, 5-11 participants) and discussion groups (n = 2, 18-25 participants) were organized with women from three indigenous ethnic groups residing in rural areas in Mexico, after they were provided with free, self-sampled HPV tests. These groups are low-income, underserved by healthcare and have historically been on the receiving end of racism and social exclusion. Descriptive, qualitative content analysis was done, including two cycles of coding. RESULTS: Interview and focus/discussion group data indicate women had limited understanding of HPV's role in cervical cancer etiology. They identified HPV's existence, that cytology detects cervical cancer, the need for regular testing and that cervical cancer is sexually transmitted. Organizational barriers to clinic-based cytology included irregular supplies of disposable speculums, distance to clinics and lack of clear communication by healthcare personnel. Women considered self-collected HPV-testing easy, less embarrassing and less painful than cytology, an opportunity for self-care and most felt they understood how to take a self-sample after a 20-min explanation. Some women feared hurting themselves when taking the self-sample or that they would take the sample incorrectly, which they worried would make the test useless. Attending HPV-testing in groups facilitated use by allowing women to discuss their doubts and fears before doing self-collection of the sample or to ask other women who were the first to do the self-sampling what the experience had been like (whether it hurt and how easy it was). Lack of indoor bathrooms was a barrier to doing HPV self-sampling at home, when those homes were resource-poor (one-room dwellings). CONCLUSIONS: Low-income, indigenous Mexican women residing in rural, underserved areas identified their need for cervical cancer screening but encountered multiple barriers to cytology-based screening. They found a number of advantages of HPV self-sampled tests. Employing self-collected HPV-testing instead of cytology could resolve some but not all gender-related, organizational or technical quality-of-care issues within cervical cancer detection and control programs.The Hybrid Capture 2 HPV tests used in this study were generously donated by Digene Corporation. Financial support for fieldwork was provided by the National HIV and AIDS Prevention and Control Center (CENSIDA) and the National Institute of Public Health, Mexico (INSP)

Human papillomavirus testing as an optional screening tool in low-resource settings of Latin America: experience from the Latin American Screening study

Hybrid capture II (HC II) test for oncogenic human papillomaviruses (HPV) was carried out in a cohort of 4284 women at their first clinical visit. Overall prevalence of HPV was 17.1%, decreasing with age from 33.9% among women below 20 years to only 11.0% among those older than 41 years. HPV prevalence was significantly higher among current smokers (odds ratio [OR] ¼ 1.31; 95% CI 1.1–1.6), in women with two or more lifetime sexual partners (OR ¼ 1.9; 95% CI 1.6–2.4), and those women with two or more sexual partners during the past 12 months prior to examination (OR ¼ 1.6; 95% CI 1.2–2.2). HPV detection increased in parallel with increasing cytologic abnormality, being highest in women with high-grade squamous intraepithelial lesion (P ¼ 0.001). Specificity of the HPV test in detecting histologically confirmed cervical disease was 85% (95% CI 83.9–86.1). Sensitivity of the HPV test in detecting histologic abnormalities increased in parallel with disease severity, ranging from 51.5% for cervical intraepithelial neoplasia (CIN) 1 to 96.5% for CIN 3 and 100.0% for cancer, with respective decline of positive predictive value. These data suggest that HPV testing with HC II assay might be a viable screening tool among this population with relatively high prevalence of cervical disease

Evaluation of visual inspection with acetic acid (VIA), Lugol’s iodine (VILI), cervical cytology and HPV testing as cervical screening tools in Latin America

Objectives: To assess the performance indicators of visual inspection with acetic acid (VIA) and visual inspection with Lugol’s iodine (VILI) in four Latin American centres participating in the ongoing Latin AMerican Screening (LAMS) study, in settings with moderate incidence of cervical disease and with poorly to moderately well-organized cervical cancer screening. Setting: Three Brazilian centres (São Paulo, Campinas and Porto Alegre) and one Argentine centre (Buenos Aires) recruited a total of 11,834 healthy women to undergo VIA, VILI, conventional Pap smear and Hybrid Capture II (HCII). Methods: Women who had a positive result from any of these tests were subjected to colposcopy and biopsies (if necessary), and women with high-grade cervical intraepithelial neoplasia (CIN) were properly treated. To control for verification bias, 5% of women with normal tests were referred for colposcopy, as were 20% of HCII-negative women. Results: Data on VIA (n = 11,834), VILI (n = 2994), conventional Pap smear (n = 10,138) and HCII (n = 4195) were available for test comparisons, calculating sensitivity, specificity, and positive and negative predictive values. Overall test positivity was 11.6% for VIA, 23.0% for VILI, 2.2% for Pap smear (LSIL threshold), 1.1% for Pap smear (HSIL threshold) and 17.1% for HCII. VIA was positive in 61.8% of the women with CIN 1, 57.0% of those with CIN 2, 35.0% of women with CIN 3 and in 21 of 28 (75%) of women with cancer. Approximately 10% of women with no detectable disease had an abnormal VIA. Regarding VILI, 83.3% of women diagnosed with CIN 1 and 62.5% of those with CIN 3 had an abnormal test. VILI failed to detect one of three cases of cancer. Both the sensitivity, specificity and positive predictive value of VIA and VILI in detecting CIN 2 or CIN 3 could be significantly improved depending on the combination with Pap smear or HCII (sensitivity up to 100.0% and specificity up to 99.8%). Conclusions: The LAMS study failed to reproduce the performance figures obtained with VIA and VILI (as stand-alone tests) in some other settings, where the prevalence of cervical disease was higher. However, a combined use of VIA or VILI with the Pap test or HCII allowed specific detection of cervical abnormalities.European Union (EU) - INCO-DEV Programme - Contract# ICA4-CT-2001-10013

Safety of screening with Human papillomavirus testing for cervical cancer at three-year intervals in a high-risk population: experience from the LAMS study

To assess whether human papillomavirus (HPV) testing is a safe enough approach to warrant extension of the screening intervals of baseline Papanicolaou (Pap)-/HPV- women in low-income settings.European Commission, INCO-DEV Programme (Contract # ICA4-CT-2001-10013). The generous contribution from DIGENE Inc. (USA) donating the HC 2 test

SPADnet: Embedded coincidence in a smart sensor network for PET applications

n this paper we illustrate the core technologies at the basis of the European SPADnet project (www.spadnet.eu), and present the corresponding first results. SPADnet is aimed at a new generation of MRI-compatible, scalable large area image sensors, based on CMOS technology, that are networked to perform gamma-ray detection and coincidence to be used primarily in (Time-of-Flight) Positron Emission Tomography (PET). The project innovates in several areas of PET systems, from optical coupling to single-photon sensor architectures, from intelligent ring networks to reconstruction algorithms. In addition, SPADnet introduced the first computational model enabling study of the full chain from gamma photons to network coincidence detection through scintillation events, optical coupling, etc

A Chemocentric Approach to the Identification of Cancer Targets

A novel chemocentric approach to identifying cancer-relevant targets is introduced. Starting with a large chemical collection, the strategy uses the list of small molecule hits arising from a differential cytotoxicity screening on tumor HCT116 and normal MRC-5 cell lines to identify proteins associated with cancer emerging from a differential virtual target profiling of the most selective compounds detected in both cell lines. It is shown that this smart combination of differential in vitro and in silico screenings (DIVISS) is capable of detecting a list of proteins that are already well accepted cancer drug targets, while complementing it with additional proteins that, targeted selectively or in combination with others, could lead to synergistic benefits for cancer therapeutics. The complete list of 115 proteins identified as being hit uniquely by compounds showing selective antiproliferative effects for tumor cell lines is provided