A data-driven spike sorting feature map for resolving spike overlap in the feature space.

Objective.Spike sorting is the process of extracting neuronal action potentials, or spikes, from an extracellular brain recording, and assigning each spike to its putative source neuron. Spike sorting is usually treated as a clustering problem. However, this clustering process is known to be affected by overlapping spikes. Existing methods for resolving spike overlap typically require an expensive post-processing of the clustering results. In this paper, we propose the design of a domain-specific feature map, which enables the resolution of spike overlap directly in the feature space.Approach.The proposed domain-specific feature map is based on a neural network architecture that is trained to simultaneously perform spike sorting and spike overlap resolution. Overlapping spikes clusters can be identified in the feature space through a linear relation with the single-neuron clusters for which the neurons contribute to the overlapping spikes. To aid the feature map training, a data augmentation procedure is presented that is based on biophysical simulations.Main results.We demonstrate the potential of our method on independent and realistic test data. We show that our novel approach for resolving spike overlap generalizes to unseen and realistic test data. Furthermore, the sorting performance of our method is shown to be similar to the state-of-the-art, but our method does not assume the availability of spike templates for resolving spike overlap.Significance.Resolving spike overlap directly in the feature space, results in an overall simplified spike sorting pipeline compared to the state-of-the-art. For the state-of-the-art, the overlapping spike snippets exhibit a large spread in the feature space and do not appear as concentrated clusters. This can lead to biased spike template estimates which affect the sorting performance of the state-of-the-art. In our proposed approach, overlapping spikes form concentrated clusters and spike overlap resolution does not depend on the availability of spike templates.

[Stress in the dental practice: 'Suddenly I wasn't able to work anymore']. / Stress in de tandartspraktijk: 'Ineens lukte werken niet meer'.

Recent research indicates 20% of dentists to experience a high degree of stress, physical pain and distress, and insomnia, which is associated with loss of productivity, both in quantity and quality. Physical distress and pain, but also difficulties with colleagues, demanding patients or loss of productivity are clearly associated with the prevalence of stress. Stress complaints are often recognised too late. 2 fictitious cases from the daily practice of occupational health experts/ergonomists are discussed. The first case concerns a 45-year-old dentist who was referred to an occupational health expert regarding severe fatigue, listlessness and a sense of loss of control. After the occupational health expert had inventoried his full workload, it was shown not to have increased. With the help of relaxation therapy, a professional organiser and an organisational and business psychologist, the dentist was able to return to work full time after 9 months. In the second case, a 55-year-old endodontist presented with neck pain. The occupational health expert/ergonomist observed postural problems and stress. The client reported she suffered from fatigue. The endodontist did not acknowledge these stress issues and wanted to address improvement of posture in particular, which was effective. The occupational health expert was nevertheless able to introduce measures to reduce stress and fatigue; after some time, the endodontist enjoyed her return to work.

Morphine, a potential inhibitor of myeloperoxidase activity.

Morphine is an opioid alkaloid commonly used in clinical practice for its analgesic properties. The phenolic hydroxyl group of that phenanthrene derivative is pivotal for binding to opioid receptors but it may also be responsible for the antioxidant behavior of morphine reported in several in vitro experiments. In this study, we assessed the effect of morphine on myeloperoxidase (MPO), a hemic enzyme from azurophilic granules of polymorphonuclear neutrophils involved in the production of cytotoxic and microbicidal reactive oxidants during inflammatory response. Specific immunological extraction followed by enzyme detection (SIEFED) and molecular modeling (docking) were performed to study the potential anti-catalytic action of morphine on MPO in comparison with the inhibitory effects of reference antioxidant molecules quercetin, gallic acid and ascorbic acid. The reducing action of morphine on the MPO peroxidase cycle has been investigated using electron paramagnetic resonance (EPR) and UV-visible absorption spectroscopy. Morphine acted as a reducing substrate in the peroxidase cycle of MPO and therefore protected the enzyme against the suicide action of its natural substrate, hydrogen peroxide. The SIEFED experiments associated with the docking study, further demonstrated a lack of strong and sustained anti-catalytic activity of morphine. In summary, from the results of this study, it appears that morphine acts as a weak and reversible inhibitor of MPO that may nonetheless contribute to immunomodulatory and antioxidant effects of this opioid analgesic in vivo.

The PDGFRα-laminin B1-keratin 19 cascade drives tumor progression at the invasive front of human hepatocellular carcinoma.

Human hepatocellular carcinomas (HCCs) expressing the biliary/hepatic progenitor cell marker keratin 19 (K19) have been linked with a poor prognosis and exhibit an increase in platelet-derived growth factor receptor α (PDGFRα) and laminin beta 1 (LAMB1) expression. PDGFRα has been reported to induce de novo synthesis of LAMB1 protein in a Sjogren syndrome antigen B (La/SSB)-dependent manner in a murine metastasis model. However, the role of this cascade in human HCC remains unclear. This study focused on the functional role of the PDGFRα-La/SSB-LAMB1 pathway and its molecular link to K19 expression in human HCC. In surgical HCC specimens from a cohort of 136 patients, PDGFRα expression correlated with K19 expression, microvascular invasion and metastatic spread. In addition, PDGFRα expression in pre-operative needle biopsy specimens predicted poor overall survival during a 5-year follow-up period. Consecutive histological staining demonstrated that the signaling components of the PDGFRα-La/SSB-LAMB1 pathway were strongly expressed at the invasive front. K19-positive HCC cells displayed high levels of α2ß1 integrin (ITG) receptor, both in vitro and in vivo. In vitro activation of PDGFRα signaling triggered the translocation of nuclear La/SSB into the cytoplasm, enhanced the protein synthesis of LAMB1 by activating its internal ribosome entry site, which in turn led to increased secretion of laminin-111. This effect was abrogated by the PDGFRα-specific inhibitor crenolanib. Importantly LAMB1 stimulated ITG-dependent focal adhesion kinase/Src proto-oncogene non-receptor tyrosine kinase signaling. It also promoted the ITG-specific downstream target Rho-associated coiled-coil containing protein kinase 2, induced K19 expression in an autocrine manner, invadopodia formation and cell invasion. Finally, we showed that the knockdown of LAMB1 or K19 in subcutaneous xenograft mouse models resulted in significant loss of cells invading the surrounding stromal tissue and reduced HepG2 colonization into lung and liver after tail vein injection. The PDGFRα-LAMB1 pathway supports tumor progression at the invasive front of human HCC through K19 expression.

Single-sided deafness affects language and auditory development - a case-control study.

OBJECTIVES: To examine auditory, linguistic and cognitive outcomes of children with single-sided deafness (SSD). An increasing body of research suggests that children with SSD lag behind with respect to their normal hearing (NH) peers. In this study, we tap into certain developmental skills. DESIGN: Case-control study. PARTICIPANTS: Twenty-one children with SSD between 5 and 15 years of age participated. Per child with SSD, two NH control children were matched on age and gender. OUTCOME MEASURES: Morphology, syntax and vocabulary were examined, and performance was assessed in depth by focusing on subskills and type of errors made. Furthermore, tests of short-term and working memory were conducted, and aspects of hearing disability were assessed by means of the speech spatial and qualities of hearing questionnaire (SSQ). MAIN RESULTS: The children with SSD lagged behind in their scores on the three language tests and showed some differences to the NH group concerning type of errors and difficulty of the several subskills. Furthermore, scores on the SSQ indicated that in daily life, the children with SSD experience problems in spatial hearing and in understanding speech in noisy situations and that the effort they have to put into listening and in understanding speech is considerably greater than in NH children. CONCLUSIONS: This study showed differences between children with SSD and NH children on several language skills and on auditory behaviour. Possibly, early intervention could prevent such language difficulties and minimise problems with spatial hearing and speech understanding.

Predictive factors of speech understanding in adults with cochlear implants.

OBJECTIVE: The aim of this study was to analyse the factors that influenced speech recognition scores in quiet conditions and speech reception threshold levels (SRT) in fixed noise conditions, after cochlear implant (CI) surgery in adults with postlinguistic deafness. STUDY DESIGN: Combined retrospective and prospective study in a tertiary referral centre. METHODS: We included 66 patients that received implants between 2002 and 2013. We retrospectively collected speech recognition scores and 14 demographic, audiological, and technical factors, including gender, age at implantation, aetiology, hearing loss progression, preoperative Pure Tone Average (PTA), hearing loss onset age and duration, duration and use of hearing aids (HAs); implantation in the best or worst ear; implantation on the right or left side; use of HA after implantation; and the duration and type of CI. We prospectively tested a subgroup of 21 patients for SRT in fixed noise. RESULTS: The hearing loss duration significantly affected speech recognition scores in quiet conditions (H (4) = 10.567, p =0.032) and SRTs in fixed noise conditions (rs = 0.466, p = 0.033). The PTA of the better ear significantly affected only the SRT in fixed noise conditions (rs = 0.57 1, p = 0.007). CONCLUSION: The duration of hearing loss and the PTA of the best ear had significant effects on the outcomes of speech recognition and SRT in quiet and fixed noise conditions, respectively. These findings are important for counselling CI candidates. Further studies in larger study populations are warranted.

Speech-in-noise testing as a marker for noise-induced hearing loss and tinnitus.

Speech-in-noise testing as a marker for noise-induced hearing loss and tinnitus. Noise-induced hearing loss and tinnitus are auditory complaints that often co-occur. Often, there is no immediate indication of changes in the pure tone audiogram. Patients can still have clinically normal hearing thresholds while clearly experiencing reduced speech comprehension. This might be explained by the process of neurodegeneration of the innervated dendrites of the auditory nerve fibres and secondary degeneration of spiral ganglion neurons. Subsequent maladaptive neuronal plasticity of the central auditory system can induce tinnitus. Standard hearing testing is no longer sufficient in these patients. Therefore more complex tasks, such as speech-in-noise tests, might be valuable extensions to the standard hearing tests. We carried out a prospective investigation of the influence of tinnitus upon speech comprehension in noise and the effectiveness of speech-in-noise testing, using the Flemish version of the digit triplet test (DTT). Thirty-seven patients with mild noise-induced hearing loss, tinnitus complaints and clinically normal pure tone thresholds completed the DTT and filled in two tinnitus enquiries. A statistically significant (p=0.026) correlation between the averaged high PTA, 2,z and the averaged SRT across ears on the DTT was found. There also seems to be a slight influence of tinnitus onset on the SRT score.

Auditory neuropathy/dyssynchrony revisited.

Auditory neuropathy/dyssynchrony (AN/AD) is a relatively, recently described diagnostic term. It describes a disorder characterised by detectable otoacoustic emissions and/or cochlear microphonics, combined with abnormal or absent auditory brainstem responses and deficient speech understanding. Consequently, the patient's cognitive responses are inconsistent with a behavioural tone audiogram. This review describes the epidemiology, pathogenesis, diagnosis, and treatment of AN/AD. We have focused on the diagnostic pathway, because diagnosis is sometimes difficult, and recent research has provided important insights into the aetiopathology of the disease. The diagnostic tools for AN/AD currently used in our department will be demonstrated in a clinical case. It is very important to recognise AN/AD and provide patient counselling and support as early as possible, due to the potentially major influence of this disorder on a patient's social life and language acquisition.

Epithelial-mesenchymal transition during invasion of cutaneous squamous cell carcinoma is paralleled by AKT activation.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is required for tumour invasion and dissemination to occur. OBJECTIVES: To investigate EMT during invasion of cutaneous squamous cell carcinoma (cSCC) and the involvement of AKT. METHODS: Using a tissue microarray, we measured expression of EMT-markers and AKT activation in 140 samples from patients with skin cancer and matched samples of normal skin adjacent to cSCC in cSCC in situ (cSCCIS) and in invasive cSCC. We investigated EMT using functional assays and the expression of EMT markers in an isogenic skin cancer progression model using cell lines derived from dysplastic forehead skin (PM1), primary invasive cSCC (MET1) and its lymph node metastasis (MET4). This model was used to investigate AKT-specific inhibition of the EMT process. RESULTS: In comparison with normal skin, and normal skin plus cSCCIS, the invasive cSCCs show significantly increased vimentin expression, decreased E-cadherin expression and increased expression of the active form of AKT. In the cell culture model, the primary MET1 cells display the lowest adhesion potential, the highest migratory and invasive ability through a Matrigel-coated porous membrane, the highest expression of EMT markers vimentin and Slug and the lowest expression of the epithelial marker E-cadherin. Pharmacological AKT inhibition in this model suppressed EMT mechanisms. CONCLUSIONS: AKT may serve as a therapeutic target to avoid dissemination of cSCC cells.

Avalanches, breathers, and flow reversal in a continuous Lorenz-96 model.

For the discrete model suggested by Lorenz in 1996, a one-dimensional long-wave approximation with nonlinear excitation and diffusion is derived. The model is energy conserving but non-Hamiltonian. In a low-order truncation, weak external forcing of the zonal mean flow induces avalanchelike breather solutions which cause reversal of the mean flow by a wave-mean flow interaction. The mechanism is an outburst-recharge process similar to avalanches in a sandpile model.

Evidence for a fluctuation theorem in an atmospheric circulation model.

An investigation of the distribution of finite time trajectory divergence is performed on an atmospheric global circulation model. The distribution of the largest local Lyapunov exponent shows a significant probability for negative values over time spans up to 10 days. This effect is present for resolutions up to wave numbers ℓ=42 (≈250 km). The probability for a negative local largest Lyapunov exponent decreases over time, similarly to the predictions of the fluctuation theorem for entropy production. The model used is hydrostatic with variable numbers of vertical levels and different horizontal resolutions.

Newborn hearing screening and cochlear implantation: impact on spoken language development.

OBJECTIVES: This study retrospectively evaluates the effect of newborn hearing screening on age at diagnosis, age at cochlear implantation and spoken language development in severely hearing-impaired children. METHODS: Age at diagnosis, age at cochlear implantation and language development were evaluated in a group of early screened (n = 149) and a group of late screened (n = 139) severely hearing-impaired children. Language outcomes were quantified as language quotients (LQs) on the Reynell Developmental Language Scales and Schlichting Expressive Language Test at 1,2, and 3 years after cochlear implantation. RESULTS: Early screened children were significantly younger than late screened children at the time of hearing loss diagnosis and cochlear implantation. Furthermore, early screening was associated with better receptive and expressive spoken language skills after cochlear implantation. CONCLUSION: The results of this retrospective study indicate that the newborn hearing screening program in Flanders and The Netherlands resulted in earlier intervention in deaf children, which beneficially influenced spoken language development.

New precision measurements of the 235U(n,γ) cross section.

The neutron capture cross section of (235)U was measured for the neutron incident energy region between 4 eV and 1 MeV at the DANCE facility at the Los Alamos Neutron Science Center with an unprecedented accuracy of 2-3% at 1 keV. The new methodology combined three independent measurements. In the main experiment, a thick actinide sample was used to determine neutron capture and neutron-induced fission rates simultaneously. In the second measurement, a fission tagging detector was used with a thin actinide sample and detailed characteristics of the prompt-fission gamma rays were obtained. In the third measurement, the neutron scattering background was characterized using a sample of (208)Pb. The relative capture cross section was obtained from the experiment with the thick (235)U sample using a ratio method after the subtraction of the fission and neutron scattering backgrounds. Our result indicates errors that are as large as 30% in the 0.5-2.5 keV region, in the current knowledge of neutron capture as embodied in major nuclear data evaluations. Future modifications of these databases using the improved precision data given herein will have significant impacts in neutronics calculations for a variety of nuclear technologies.

Molecular identification of hybrids of the invasive gibel carp Carassius auratus gibelio and crucian carp Carassius carassius in Swedish waters.

Both mitochondrial DNA sequence and two nuclear microsatellite markers were used to confirm the identity of the first record of Carassius auratus gibelio in the western (Swedish) Baltic Sea region. A total of 49 fishes were analysed, where 22 were from three Swedish sites connected to the Baltic Sea. The D-loop mitochondrial DNA sequences showed that 16 of 22 Swedish fishes were related to C. a. gibelio. The phylogenetic analysis of these sequences showed that these fish are probably not native, but represent different lineages of C. a. gibelio from China, Japan and Russia. All except three of these 16 fishes had microsatellite alleles suggesting hybridization with Carassius carassius. These findings suggest that a cryptic invasion of C. a. gibelio might be in progress.

Abrupt change in radiation-width distribution for 147Sm neutron resonances.

We obtained the total radiation widths of s-wave resonances through an R-matrix analysis of (147)Sm(n,γ) cross sections. Distributions of these widths differ markedly for resonances below and above E(n)=300 eV, which is in stark contrast to long-established theory. We show that this change, as well as a similar change in the neutron-width distribution reported previously, is reflected in abrupt increases in both the average (147)Sm(n,γ) cross section and fluctuations about the average near 300 eV. Such effects could have important consequences for applications such as nuclear astrophysics and nuclear criticality safety.

Synthesis and inhibition study of monoamine oxidase, indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase by 3,8-substituted 5H-indeno[1,2-c]pyridazin-5-one derivatives.

Previous studies on 5H-indeno[1,2-c]pyridazin-5-one derivatives as inhibitors of MAO-B revealed that it was possible to increase the MAO-B inhibitory potency of 5H-indeno[1,2-c]pyridazin-5-ones by substituting the central heterocycle in the 3-position or C-8 with lipophilic groups which occupy the substrate cavity or the entrance of the binding site, respectively. Here, four new 5H-indeno[1,2-c]pyridazin-5-one derivatives containing lipophilic groups at both positions were synthesized and their inhibitory potency against human monoamine oxidase A and B were evaluated. Selectivity of these compounds against IDO and TDO, two enzymes sharing substrate similarity with MAO and involved in the serotonergic and kynurenine pathways was also studied. All compounds showed higher activity and selectivity against MAO-B, the most effective one being 3-methyl-8-meta-chlorobenzyloxy-5H-indeno[1,2-c]pyridazin-5-one (9a) which was shown to be a competitive inhibitor with a K(i) value of 0.11 µM. Replacing the methyl group in the 3-position with a meta-CF(3)-phenyl group (7a, 7b and 7c) abolished the inhibitory potency against MAO-B. Indeed, the substitution of the 5H-indeno[1,2-c]pyridazin-5-one core in the 3-position dramatically influences the MAO-inhibiting properties of these compounds. Molecular docking studies of 9a within MAO-B suggest that the 5H-indeno[1,2-c]pyridazin-5-one scaffold is well stabilized into the substrate cavity with the meta-chlorobenzyloxy side chain extending towards a rather hydrophobic pocket at the entrance cavity.

Study on the applicability of instrumental measures for black-box evaluation of static feedback control in hearing aids.

Presented is a report on black-box evaluation of feedback control systems for commercial hearing aids. The aim of the study is to examine the ability of existing instrumental measures to quantify the performance of the feedback control system in black-box settings and on realistic signals, when more than one element of the signal processing chain may be active (compression, noise suppression, microphone directionality, etc.). The evaluation is carried out on 6 different hearing aids and for 10 measures. Thereby it is possible to see which measure is best suited to measuring which specific characteristic of the feedback control system, and serves as a beginning for conducting perceptual tests. The study uses static (but variable) feedback paths and is based on signals recorded from the in-ear microphone of an artificial head, on which the hearing instruments are mounted.

Functional benefit of the bone-anchored hearing aid with different auditory profiles: objective and subjective measures.

OBJECTIVES: To examine sentence recognition and self-report outcomes in hearing-impaired persons with different auditory profiles and who were fitted unilaterally with a bone-anchored hearing aid. STUDY-DESIGN: Prospective cohort study. SETTING: Tertiary referral unit. PATIENTS: Data were collected of six patients with single-sided deafness (SSD), seven with a mild to severe hearing loss at the bone-anchored hearing aid side and (near-)normal hearing at the other side and six with a severe bilateral hearing loss. MAIN OUTCOME MEASUREMENTS: Sound field thresholds, and sentence recognition in noise (presented from different angles) with bone-anchored hearing aid, without bone-anchored hearing aid and with bone-anchored hearing aid and other ear occluded. In addition, the Speech, Spatial and Qualities of hearing scale and the Abbreviated Profile of Hearing Aid Benefit questionnaire were administered as self-report measures. RESULTS: Patients with single-sided deafness listened mainly with their non-bone-anchored hearing aid ear, although the bone-anchored hearing aid lifted the head shadow effect. Patients with mild to severe hearing loss at the bone-anchored hearing aid side and (near-)normal hearing at the other side performed significantly differently in aided and unaided conditions and even regained limited binaural sensitivity with the device. The latter was also true for the patients with severe bilateral hearing loss. However, their hearing loss at the non-bone-anchored hearing aid side was too great to contribute to hearing and they listened predominantly with their bone-anchored hearing aid. Self-report outcomes provided useful information on hearing disability, although this information was not significantly differently for the 3 groups of patients. CONCLUSIONS: The bone-anchored hearing aid enhanced performance in different hearing configurations, albeit to different extents.

Fast and accurate peanut allergen detection with nanobead enhanced optical fiber SPR biosensor.

This paper is the first report of a fiber optic SPR biosensor with nanobead signal enhancement. We evaluated the system with a bioassay for the fast and accurate detection of peanut allergens in complex food matrices. Three approaches of an immunoassay to detect Ara h1 peanut allergens in chocolate candy bars were compared; a label-free assay, a secondary antibody sandwich assay and a nanobead enhanced assay. Although label-free detection is the most convenient, our results illustrate that functionalized nanobeads can offer a refined solution to improve the fiber SPR detection limit. By applying magnetite nanoparticles as a secondary label, the detection limit of the SPR bioassay for Ara h1 was improved by two orders of magnitude from 9 to 0.09 µg/mL. The super paramagnetic character of the nanoparticles ensured easy handling. The SPR fibers could be regenerated easily and one fiber could be reused for up to 35 times without loss of sensitivity. The results were benchmarked against a commercially available polyclonal ELISA kit. An excellent correlation was found between the Ara h1 concentrations obtained with the ELISA and the concentrations measured with the SPR fiber assay. In addition, with the SPR fiber we could measure the samples twice as fast as compared to the fastest ELISA protocol. Since the dipstick fiber has no need for microchannels that can become clogged, time consuming rinsing step could be avoided. The linear dynamic range of the presented sensor was between 0.1 and 2 µg/mL, which is considerably larger than the ELISA benchmark.