An extended case study on the phenomenology of sequence-space synesthesia

Investigation of synesthesia phenomenology in adults is needed to constrain accounts of developmental trajectories of this trait. We report an extended phenomenological investigation of sequence-space synesthesia in a single case (AB). We used the Elicitation Interview (EI) method to facilitate repeated exploration of AB's synesthetic experience. During an EI the subject's attention is selectively guided by the interviewer in order to reveal precise details about the experience. Detailed analysis of the resulting 9 h of interview transcripts provided a comprehensive description of AB's synesthetic experience, including several novel observations. For example, we describe a specific spatial reference frame (a "mental room") in which AB's concurrents occur, and which overlays his perception of the real world (the "physical room"). AB is able to switch his attention voluntarily between this mental room and the physical room. Exemplifying the EI method, some of our observations were previously unknown even to AB. For example, AB initially reported to experience concurrents following visual presentation, yet we determined that in the majority of cases the concurrent followed an internal verbalization of the inducer, indicating an auditory component to sequence-space synesthesia. This finding is congruent with typical rehearsal of inducer sequences during development, implicating cross-modal interactions between auditory and visual systems in the genesis of this synesthetic form. To our knowledge, this paper describes the first application of an EI to synesthesia, and the first systematic longitudinal investigation of the first-person experience of synesthesia since the re-emergence of interest in this topic in the 1980's. These descriptions move beyond rudimentary graphical or spatial representations of the synesthetic spatial form, thereby providing new targets for neurobehavioral analysis

Seeing with sound? Exploring different characteristics of a visual-to-auditory sensory substitution device

Sensory substitution devices convert live visual images into auditory signals, for example with a web camera (to record the images), a computer (to perform the conversion) and headphones (to listen to the sounds). In a series of three experiments, the performance of one such device (‘The vOICe’) was assessed under various conditions on blindfolded sighted participants. The main task that we used involved identifying and locating objects placed on a table by holding a webcam (like a flashlight) or wearing it on the head (like a miner’s light). Identifying objects on a table was easier with a hand-held device, but locating the objects was easier with a head-mounted device. Brightness converted into loudness was less effective than the reverse contrast (dark being loud), suggesting that performance under these conditions (natural indoor lighting, novice users) is related more to the properties of the auditory signal (ie the amount of noise in it) than the cross-modal association between loudness and brightness. Individual differences in musical memory (detecting pitch changes in two sequences of notes) was related to the time taken to identify or recognise objects, but individual differences in self-reported vividness of visual imagery did not reliably predict performance across the experiments. In general, the results suggest that the auditory characteristics of the device may be more important for initial learning than visual associations

Resolving the masers in M82

Despite first being detected in the 1970s, surprisingly little is known about the OH main line maser population in the nearby starburst galaxy M82. Sometimes referred to as 'kilomasers', they have isotropic luminosities intermediate between Galactic masers and those found in more distant megamasers. Several observations have been carried by this group over the last ten years in an attempt to get a better handle on their nature. High velocity resolution VLA observations in 2006 showed that almost all of the maser spots, distributed across the central arcminute of the galaxy, were apparently coincident with background continuum features, and a handful displayed multiple velocity components. The majority of those with velocity structure are located on a blue-shifted arc in the pv-plane, spatially located on an arc northward of the peculiar source known as B41.95+57.5. Now, new results from high spatial and spectral resolution observations with the EVN have resolved several of these masers into multiple spatial components for the first time. The maser emission is compared with known continuum sources in the galaxy, and we conclude that at least some of the maser emission is from high-gain maser action.Comment: Six pages, one table, one figure. To appear in proceedings of the 11th EVN Symposium (Bordeaux, 9-12 October 2012

Disruption of IGF-1R Signaling Increases TRAIL-Induced Apoptosis: A New Potential Therapy for the Treatment of Melanoma

Resistance of cancer cells to apoptosis is dependent on a balance of multiple genetic and epigenetic mechanisms, which up-regulate efficacy of the surviving growth factor-receptor signaling pathways and suppress death-receptor signaling pathways. The Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling pathway is highly active in metastatic melanoma cells by mediating downstream activation of PI3K-AKT and MAPK pathways and controlling general cell survival and proliferation. In the present study, we used human melanoma lines with established genotypes that represented different phases of cancer development: radial-growth-phase WM35, vertical-growth-phase WM793, metastatic LU1205 and WM9 [1]. All these lines have normal NRAS. WM35, WM793, LU1205 and WM9 cells have mutated BRAF (V600E). WM35 and WM9 cells express normal PTEN, while in WM793 cells PTEN expression is down-regulated; finally, in LU1205 cells PTEN is inactivated by mutation. Cyclolignan picropodophyllin (PPP), a specific inhibitor of IGF-1R kinase activity, strongly down-regulated the basal levels of AKT activity in WM9 and in WM793 cells, modestly does so in LU1205, but has no effect on AKT activity in the early stage WM35 cells that are deficient in IGF-1R. In addition, PPP partially down-regulated the basal levels of active ERK1/2 in all lines used, highlighting the role of an alternative, non-BRAF pathway in MAPK activation. The final result of PPP treatment was an induction of apoptosis in WM793, WM9 and LU1205 melanoma cells. On the other hand, dose-dependent inhibition of IGF-1R kinase activity by PPP at a relatively narrow dose range (near 500 nM) has different effects on melanoma cells versus normal cells, inducing apoptosis in cancer cells and G2/M arrest of fibroblasts. To further enhance the pro-apoptotic effects of PPP on melanoma cells, we used a combined treatment of TNF-Related Apoptosis-Inducing Ligand (TRAIL) and PPP. This combination substantially increased death by apoptosis for WM793 and WM9 cells, but did so only modestly for LU1205 cells with very high basal activity of AKT. The ultimate goal of this direction of research is the discovery of a new treatment method for highly resistant human metastatic melanomas. Our findings provide the rationale for further preclinical evaluation of this novel treatment

An excursion set model of the cosmic web: The abundance of sheets, filaments and halos

We discuss an analytic approach for modeling structure formation in sheets, filaments and knots. This is accomplished by combining models of triaxial collapse with the excursion set approach: sheets are defined as objects which have collapsed along only one axis, filaments have collapsed along two axes, and halos are objects in which triaxial collapse is complete. In the simplest version of this approach, which we develop here, large scale structure shows a clear hierarchy of morphologies: the mass in large-scale sheets is partitioned up among lower mass filaments, which themselves are made-up of still lower mass halos. Our approach provides analytic estimates of the mass fraction in sheets, filaments and halos, and its evolution, for any background cosmological model and any initial fluctuation spectrum. In the currently popular $\Lambda$CDM model, our analysis suggests that more than 99% of the cosmic mass is in sheets, and 72% in filaments, with mass larger than $10^{10} M_{\odot}$ at the present time. For halos, this number is only 46%. Our approach also provides analytic estimates of how halo abundances at any given time correlate with the morphology of the surrounding large-scale structure, and how halo evolution correlates with the morphology of large scale structure.Comment: 22 pages, 7 figures, Accepted for publication in Ap

Semi-Permanent Vacuum Closure with Multiple Retubulation Capability

A vacuum system (20) includes an enclosure (22) having a vacuum-tight wall (26) and an internally threaded aperture (66) through the wall (26). A tip-off fitting (24) has a base (50) with a bore (52) therethrough, a hollow tube (62) fixed to the base (50) with a vacuum-tight seal, such that an interior (64) of the tube (62) is in communication with the bore (52) in the base (50), and an external thread (58) on the exterior of the base (50). The external thread (58) on the exterior of the base (50) is dimensioned to threadably engage the internal thread (68) on the aperture (66). There is a disengageable vacuum sealant (70) such as a layer of indium metal between the external thread (58) of the base (50) and the internal thread (68) of the aperture (66). The vacuum system (20) is evacuated through the tip-off fitting (24) and sealed by closing off the hollow tube (62). At a later time, the vacuum system can be brought to atmospheric pressure and then reseated by replacing the tip-off fitting with another tip-off fitting and repeating the evacuation and sealing

Long-term follow up to assess criteria for ovarian tissue cryopreservation for fertility preservation in young women and girls with cancer

Funding: K.D. is supported by a CRUK grant (C157/A25193). This work was undertaken in part in the MRC Centre for Reproductive Health, (supported by MRC grant MR/N022556/1). R.A.A. has received consulting fees from Ferring and Roche Diagnostics; payment from Merck and IBSA for educational events; and laboratory materials from Roche Diagnostics.STUDY QUESTION Do the Edinburgh Selection Criteria correctly identify female cancer patients under the age of 18 who are at risk of premature ovarian insufficiency (POI) as candidates for ovarian tissue cryopreservation (OTC)? SUMMARY ANSWER Patient assessment using these criteria accurately identifies those at risk of POI, who can be offered OTC and future transplantation as a means of fertility preservation. WHAT IS KNOWN ALREADY Treatment for childhood cancer can have adverse consequences on future fertility; at the time of diagnosis, fertility risk assessment should be undertaken in order to identify patients to whom fertility preservation should be offered. The Edinburgh selection criteria, based on planned cancer treatment and patient health status, are utilized to identify those at high risk and therefore eligible for OTC. However, this procedure is not without risk and there are few data on the efficacy of the procedure in prepubertal patients. As such, long-term follow-up of reproductive outcomes is necessary, to ensure that OTC is being offered appropriately. STUDY DESIGN, SIZE, DURATION Cohort study encompassing all females diagnosed with cancer under the age of 18 in South East Scotland, from 1 January 1996 to 30 April 2020. Patients were followed up for reproductive outcomes to assess for diagnosis of POI. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 638 eligible patients were identified; patients under the age of 12 or deceased before the age of 12 were excluded from the study, leaving a study population of 431 patients. Electronic records were reviewed for reproductive function, assessed by current menstruation, pregnancy (in the absence of POI diagnosis), reproductive hormone measurements, pubertal progression, or diagnosis of POI. Patients on hormonal contraception (other than for treatment of POI or panhypopituitarism with no history of gonadatoxic treatment) were excluded from analysis (n = 9). Analysis on remaining 422 patients was carried out using the Kaplan–Meier methods, with POI as the defined event, and Cox proportional hazards model. MAIN RESULTS AND THE ROLE OF CHANCE In the study population of 431 patients, median ages at diagnosis and analysis were 9.8 and 22.2 years, respectively. Reproductive outcomes were unavailable in 142 patients; the assumption was made that these patients did not have POI, but a subanalysis excluding these patients was also performed. Of the 422 patients aged >12 at analysis and not taking hormonal contraception, OTC was offered to 37 patients and successfully performed in 25 patients. Of the 37 patients offered OTC (one at time of relapse), nine (24.3%) developed POI. Of the 386 not offered OTC, 11 (2.9%) developed POI. The probability of developing POI was significantly higher in those offered OTC (hazard ratio [HR] 8.7 [95% CI 3.6–21]; P < 0.0001), even when those patients with unknown outcomes were excluded from the analysis (HR 8.1 [95% CI 3.4–20]; P < 0.001). All patients offered OTC who developed POI did so after treatment for primary disease; in those not offered OTC, five patients (45.5%) developed POI after treatment for disease relapse. LIMITATIONS, REASONS FOR CAUTION A significant number of patients had unknown reproductive outcomes; many of these patients were engaged in ongoing follow-up but did not have documented reproductive assessment. This may have introduced bias to the analysis and highlights the need for reproductive follow-up as part of routine cancer aftercare. In addition, the relatively young age of the patient population and short duration of follow-up in some cases demonstrates the need for ongoing follow-up of this cohort. WIDER IMPLICATIONS OF THE FINDINGS The prevalence of POI after childhood cancer is low, but the Edinburgh selection criteria remain a robust tool for selecting those at high risk at the time of diagnosis, to offer OTC appropriately. However, disease relapse necessitating more intensive treatments remains a challenge. This study additionally highlights the importance of routine assessment and documentation of reproductive status in haematology/oncology follow-up.Publisher PDFPeer reviewe

Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease

Oxidative stress is proposed as an important factor in osteoarthritis (OA). To investigate the expression of the three superoxide dismutase (SOD) antioxidant enzymes in OA. SOD expression was determined by real-time PCR and immunohistochemistry using human femoral head cartilage. SOD2 expression in Dunkin–Hartley guinea pig knee articular cartilage was determined by immunohistochemistry. The DNA methylation status of the SOD2 promoter was determined using bisulphite sequencing. RNA interference was used to determine the consequence of SOD2 depletion on the levels of reactive oxygen species (ROS) using MitoSOX and collagenases, matrix metalloproteinase 1 (MMP-1) and MMP-13, gene expression. All three SOD were abundantly expressed in human cartilage but were markedly downregulated in end-stage OA cartilage, especially SOD2. In the Dunkin–Hartley guinea pig spontaneous OA model, SOD2 expression was decreased in the medial tibial condyle cartilage before, and after, the development of OA-like lesions. The SOD2 promoter had significant DNA methylation alterations in OA cartilage. Depletion of SOD2 in chondrocytes increased ROS but decreased collagenase expression. This is the first comprehensive expression profile of all SOD genes in cartilage and, importantly, using an animal model, it has been shown that a reduction in SOD2 is associated with the earliest stages of OA. A decrease in SOD2 was found to be associated with an increase in ROS but a reduction of collagenase gene expression, demonstrating the complexities of ROS function