Establishment of a Simple Method for Inducing Neuronal Differentiation of P19 EC Cells without Embryoid Body Formation and Analysis of the Role of Histone Deacetylase 8 Activity in This Differentiation.

P19 pluripotent embryonic carcinoma (EC) stem cells are derived from pluripotent germ cell tumours and can differentiate into three germ layers. Treatment of these cells in suspension culture with retinoic acid induces their differentiation into neurons and glial cells. Hence, these cells are an excellent in vitro model to study the transition from the upper blastoderm to the neuroectoderm. However, because of the complex nature of the techniques involved, the results are highly dependent on the skills of the experimenter. Herein, we developed a simple method to induce neuronal differentiation of adherent P19 EC cells in TaKaRa NDiff® 227 serum-free medium (originally N2B27 medium). This medium markedly induced neuronal differentiation of P19 EC cells. The addition of retinoic acid to the NDiff® 227 medium further enhanced differentiation. Furthermore, cells differentiated by the conventional method, as well as the new method, showed identical expression of the mature neuronal marker, neuronal nuclei. To determine whether our approach could be applied for neuronal studies, we measured histone deacetylase 8 (HDAC8) activity using an HDAC8 inhibitor and HDAC8-knockout P19 EC cells. Inhibition of HDAC8 activity suppressed neuronal maturation. Additionally, HDAC8-knockout cell lines showed immature differentiation compared to the wild-type cell line. These results indicate that HDAC8 directly regulates the neuronal differentiation of P19 EC cells. Thus, our method involving P19 EC cells can be used as an experimental system to study the nervous system. Moreover, this method is suitable for screening drugs that affect the nervous system and cell differentiation.

Transdifferentiation of α-1,3-galactosyltransferase knockout pig bone marrow derived mesenchymal stem cells into pancreatic ß-like cells by microenvironment modulation.

OBJECTIVE: To evaluate the pancreatic differentiation potential of α-1,3-galactosyltransferase knockout (GalTKO) pig-derived bone marrow-derived mesenchymal stem cells (BM-MSCs) using epigenetic modifiers with different pancreatic induction media. METHODS: The BM-MSCs have been differentiated into pancreatic ß-like cells by inducing the overexpression of key transcription regulatory factors or by exposure to specific soluble inducers/small molecules. In this study, we evaluated the pancreatic differentiation of GalTKO pig-derived BM-MSCs using epigenetic modifiers, 5-azacytidine (5-Aza) and valproic acid (VPA), and two types of pancreatic induction media - advanced Dulbecco's modified Eagle's medium (ADMEM)-based and N2B27-based media. GalTKO BM-MSCs were treated with pancreatic induction media and the expression of pancreas-islets-specific markers was evaluated by real-time quantitative polymerase chain reaction, Western blotting, and immunofluorescence. Morphological changes and changes in the 5'-C-phosphate-G-3' (CpG) island methylation patterns were also evaluated. RESULTS: The expression of the pluripotent marker (POU class 5 homeobox 1 [OCT4]) was upregulated upon exposure to 5-Aza and/or VPA. GalTKO BM-MSCs showed increased expression of neurogenic differentiation 1 in the ADMEM-based (5-Aza) media, while the expression of NK6 homeobox 1 was elevated in cells induced with the N2B27-based (5-Aza) media. Moreover, the morphological transition and formation of islets-like cellular clusters were also prominent in the cells induced with the N2B27-based media with 5-Aza. The higher insulin expression revealed the augmented trans-differentiation ability of GalTKO BM-MSCs into pancreatic ß-like cells in the N2B27-based media than in the ADMEM-based media. CONCLUSION: 5-Aza treated GalTKO BM-MSCs showed an enhanced demethylation pattern in the second CpG island of the OCT4 promoter region compared to that in the GalTKO BM-MSCs. The exposure of GalTKO pig-derived BM-MSCs to the N2B27-based microenvironment can significantly enhance their trans-differentiation ability into pancreatic ß-like cells.

Mechanical responses of the mechanosensitive unstructured domains in cardiac titin.

BACKGROUND INFORMATION: Titin is one of the three main filaments in cardiac sarcomere. Besides a chain of Ig domains, cardiac titin also contains a proline (P), glutamate (E), valine (V), lysine (K) (PEVK) domain and a cardiac-specific N2B domain, both are largely unstructured. While they are believed to be involved in the elastic (PEVK and N2B) and the trophic (N2B) functions of the heart, their mechanical responses in physiological level of forces remains poorly understood. RESULTS: In order to gain understanding on their mechanical responses, we used magnetic tweezers to investigate their force responses from 1 to 30 pN. We confirmed that in vitro the PEVK domain is intrinsically disordered within the force range. Surprisingly, we discovered a mechanosensitive folded element in the disordered region of N2B, ∼84 amino acids in length, which has a large folding energy of approximately -10 kB T. Based on the force responses of PEVK and N2B domains, as well as an approximated force-dependent unfolding and refolding rates of titin Ig domains, we show that the tension in cardiac titin fluctuates within 5 pN during cardiac contraction and extension cycle using Gillespie simulation algorithm. Exceptionally, the simulation shows that deletion of N2B domain results in 10-fold increase in peak force. CONCLUSION: Our results highlight a critical role that N2B may potentially play in regulating tension on cardiac titin. SIGNIFICANCE: The study provides new insights into the tension regulatory role of unstructured domains in the elastic function of the heart, which has broad implication in diastolic dysfunction and cardiac trophic mechanisms. In addition, the method can be applied to probing other unstructured mechanosensitive proteins/domains.

How can no change in an auditory stimulus generate an N2b-P3a?

The purpose of this study was to investigate the occurrence of an endogenously-evoked no-go N2b. Previous literature focused on the N2b being evoked by exogenous auditory stimuli. In this study, no-go stimuli were the absence of a gap in a 1000-ms noise burst (i.e., no-gap trials). ERPs were measured from 35 participants while performing a gap-detection task and passively listening to the same stimuli. Participants were asked to press a button when they heard a gap in the noise burst (go trials) and to withhold their button press when they did not perceive a gap in the noise burst (no-go trials). The current study's gap-detection task had predictable timing (gaps always occurred at 500 ms after noise burst onset) and high probability of gaps occurring (10:1); therefore, participants built up an expectancy that gaps would occur on most trials at 500 ms. For no-gap trials, this meant that a participant's expectancy was violated and thus a N2b-P3a response was generated. We found that all participants had N2b-P3a responses to no-gap trials. Overall, this study demonstrated that the no-go N2b-P3a response can be evoked by an endogenous signal in the form of the omission of an expected gap in noise.

The effects of attention and task-relevance on the processing of syntactic violations during listening to two concurrent speech streams.

The notion of automatic syntactic analysis received support from some event-related potential (ERP) studies. However, none of these studies tested syntax processing in the presence of a concurrent speech stream. Here we present two concurrent continuous speech streams, manipulating two variables potentially affecting speech processing in a fully crossed design: attention (focused vs. divided) and task (lexical - detecting numerals vs. syntactical - detecting syntactic violations). ERPs elicited by syntactic violations and numerals as targets were compared with those for distractors (task-relevant events in the unattended speech stream) and attended and unattended task-irrelevant events. As was expected, only target numerals elicited the N2b and P3 components. The amplitudes of these components did not significantly differ between focused and divided attention. Both task-relevant and task-irrelevant syntactic violations elicited the N400 ERP component within the attended but not in the unattended speech stream. P600 was only elicited by target syntactic violations. These results provide no support for the notion of automatic syntactic analysis. Rather, it appears that task-relevance is a prerequisite of P600 elicitation, implying that in-depth syntactic analysis occurs only for attended speech under everyday listening situations.

A serum-free and defined medium for the culture of mammalian postimplantation embryos.

Whole embryo culture (WEC) of postimplantation rodent embryos is widely used for the study of mammalian embryogenesis and developmental toxicity testing. Its major advantage is that it allows direct access to embryos for experimental manipulations and the monitoring of their consequences that would otherwise not be possible or technically difficult to perform in utero. However, a major drawback of mammalian WEC is that the culture media currently in use display batch variations and are undefined, as they contain serum or serum replacements of unknown composition. Moreover, these media possess cell-signalling activities important for embryogenesis. Therefore, reproducibility of mammalian postimplantation WEC results may be affected by batch variation and their interpretation is complicated because the experimenter is unsure whether the embryo response to experimental perturbations is solely due to their action, or modified as a result of influences from undefined substances/signaling activities present in culture media. To alleviate these problems we investigated whether N2B27, a serum-free and defined medium, can support the in vitro development of postimplantation mammalian embryos. We show that N2B27 allows pre-gastrulation mouse embryos isolated at embryonic day 5.5 to develop to advanced gastrulation, reaching the mid- and late primitive streak stages. This is the first demonstration that postimplantation mammalian embryos can develop in vitro in a defined medium in the absence of serum and provides a novel WEC system for studying developmental mechanisms and testing for developmental toxicity during the early postimplantation period.

Low contralateral neck recurrence risk with ipsilateral neck radiotherapy in N2b tonsillar squamous cell carcinoma.

OBJECTIVES: To characterize factors including nodal burden, pre-treatment imaging, and other patient factors which may influence the role of ipsilateral neck radiotherapy (IRT) in tonsillar squamous cell carcinoma (SCC) with multiple involved ipsilateral nodes. METHODS: Patients with cT1-2N0-2bM0 (AJCC 7th edition) tonsillar SCC treated with definitive radiation therapy (RT) at Duke University Medical Center from 1/1/1990-10/1/2019 were identified. Patient, tumor, and treatment characteristics were compared between those that received bilateral neck RT (BRT) versus IRT. Recurrence-free survival (RFS) was estimated with Kaplan-Meier method. A subset analysis of patients with N2b disease was performed. Patterns of recurrence were analyzed. RESULTS: 120 patients with cT1-2N0-2b tonsillar SCC were identified, including 71 with N2b disease (BRT: n = 30; IRT: n = 41). Median follow-up was 80 months (range: 7-209). No N2b patients who received IRT had > 1 cm of soft palate/base of tongue extension. N2b patients treated with IRT had a median of 3 (range 2-9) involved lymph nodes, with median largest nodal dimension of 2.8 cm (range 1.3-4.8 cm). 93 % of N2b patients who received IRT had staging by PET/CT, and 100 % received IMRT. For N2b patients treated with IRT, there were no contralateral neck recurrences, and 10 year RFS was 95 % (95 % CI 82 %-98 %). CONCLUSIONS: For patients treated with IRT for well-lateralized N2b tonsillar SCC, we observed high rates of local control with no observed contralateral neck recurrence. These data suggest that BRT is not universally necessary for patients with multiple involved ipsilateral nodes, particularly in the setting of baseline staging with PET/CT.

Pre-hatching exposure to N2B27 medium improves post-hatching development of bovine embryos in vitro.

Ungulate embryos undergo critical cell differentiation and proliferation events around and after blastocyst hatching. Failures in these processes lead to early pregnancy losses, which generate an important economic impact on farming. Conventional embryo culture media, such as SOF, are unable to support embryo development beyond hatching. In contrast, N2B27 medium supports early post-hatching development, evidencing a swift in embryonic nutritional requirements during this developmental window. Here, we investigate if earlier exposure to N2B27 could improve embryo development after hatching. Embryo culture in N2B27 from day (D) 5, 6 or 7 significantly enhanced complete hypoblast migration (>45 vs. ∼24%) and epiblast development into an embryonic disc (ED)-like structure at D12 (>40 vs. 23%), compared to embryos cultured in SOF up to D9. Culture in N2B27 from D5 significantly increased epiblast and hypoblast cell number in D8 blastocysts, but post-hatching embryos cultured in N2B27 from D5 or 6 frequently showed a disorganized distribution of epiblast cells. In conclusion, bovine embryo culture in N2B27 from D7 onwards improves subsequent post-hatching development. This improved fully in vitro system will be very useful to functionally explore cell differentiation mechanisms and the bases of early pregnancy failures without requiring animal experimentation.

Visualization and Estimation of Nasal Spray Delivery to Olfactory Mucosa in an Image-Based Transparent Nasal Model.

Background: Nose-to-brain (N2B) drug delivery offers unique advantages over intravenous methods; however, the delivery efficiency to the olfactory region using conventional nasal devices and protocols is low. This study proposes a new strategy to effectively deliver high doses to the olfactory region while minimizing dose variability and drug losses in other regions of the nasal cavity. Materials and Methods: The effects of delivery variables on the dosimetry of nasal sprays were systematically evaluated in a 3D-printed anatomical model that was generated from a magnetic resonance image of the nasal airway. The nasal model comprised four parts for regional dose quantification. A transparent nasal cast and fluorescent imaging were used for visualization, enabling detailed examination of the transient liquid film translocation, real-time feedback on input effect, and prompt adjustment to delivery variables, which included the head position, nozzle angle, applied dose, inhalation flow, and solution viscosity. Results: The results showed that the conventional vertex-to-floor head position was not optimal for olfactory delivery. Instead, a head position tilting 45-60° backward from the supine position gave a higher olfactory deposition and lower variability. A two-dose application (250 mg) was necessary to mobilize the liquid film that often accumulated in the front nose following the first dose administration. The presence of an inhalation flow reduced the olfactory deposition and redistributed the sprays to the middle meatus. The recommended olfactory delivery variables include a head position ranging 45-60°, a nozzle angle ranging 5-10°, two doses, and no inhalation flow. With these variables, an olfactory deposition fraction of 22.7 ± 3.7% was achieved in this study, with insignificant discrepancies in olfactory delivery between the right and left nasal passages. Conclusions: It is feasible to deliver clinically significant doses of nasal sprays to the olfactory region by leveraging an optimized combination of delivery variables.

Intranasal nanotherapeutics for brain targeting and clinical studies in Parkinson's disease.

Parkinson's disease (PD) is the second leading neurodegenerative disease globally, impacting the quality of life of millions of people. It is estimated that the treatment cost of PD in the USA can rise to 79 billion dollars by 2037. Limited drugs are approved by USFDA, which only provides symptomatic relief. Further, the drug efficacy is challenged due to low drug-brain concentration due to first-pass metabolism and blood-brain barrier (BBB). Intranasal drug administration can offer several advantages over systemic administration, providing efficient brain delivery. Nose-to-brain (N2B) drug delivery can enhance brain bioavailability, reduce enzymatic degradation, and reduce systemic adverse effects. However, due to poor absorption from the nasal mucosa, intranasal administration can be challenging for hydrophilic drugs. The drug mucociliary clearance, retention time, and nasal enzymatic degradation can also affect N2B drug delivery. Nanocarriers can enhance residence time, improve nasal permeation, increase brain uptake, and reduce enzymatic degradation. This review discusses the roles and applications of various N2B nanocarriers to treat PD effectively. Clinical trials of antiparkinson molecules is also covered. Lastly, safety aspects and prospects of potential nanotherapeutics for the effective treatment of PD are discussed.

The Upper Nasal Space: Option for Systemic Drug Delivery, Mucosal Vaccines and "Nose-to-Brain".

Sino-nasal disease is appropriately treated with topical treatment, where the nasal mucosa acts as a barrier to systemic absorption. Non-invasive nasal delivery of drugs has produced some small molecule products with good bioavailability. With the recent COVID pandemic and the need for nasal mucosal immunity becoming more appreciated, more interest has become focused on the nasal cavity for vaccine delivery. In parallel, it has been recognized that drug delivery to different parts of the nose can have different results and for "nose-to-brain" delivery, deposition on the olfactory epithelium of the upper nasal space is desirable. Here the non-motile cilia and reduced mucociliary clearance lead to longer residence time that permits enhanced absorption, either into the systemic circulation or directly into the CNS. Many of the developments in nasal delivery have been to add bioadhesives and absorption/permeation enhancers, creating more complicated formulations and development pathways, but other projects have shown that the delivery device itself may allow more differential targeting of the upper nasal space without these additions and that could allow faster and more efficient programs to bring a wider range of drugs-and vaccines-to market.

Convolutions in the rendition of nose to brain therapeutics from bench to bedside: Feats & fallacies.

Brain, a subtle organ of multifarious nature presents plethora of physiological, metabolic and bio-chemical convolutions that impede the delivery of biomolecules and thereby resulting in truncated therapeutic outcome in pathological conditions of central nervous system (CNS). The absolute bottleneck in the therapeutic management of such devastating CNS ailments is the BBB. Another pitfall is the lack of efficient technological platforms (due to high cost and low approval rates) as well as limited clinical trials (due to failures of neuro­leads in late-stage pipelines) for CNS disorders which has become a literal brain drain with poorest success rates compared to other therapeutic areas, owing to time consuming processes, tremendous convolutions and conceivable adverse effects. With the advent of intranasal delivery (via direct N2B or indirect nose to blood to brain), several novel drug delivery carriers viz. unmodified or surface modified nanoparticle based carriers, lipid based colloidal nanocarriers and drysolid/liquid/semisolid nanoformulations or delivery platforms have been designed as a means to deliver therapeutic agents (small and large molecules, peptides and proteins, genes) to brain, bypassing BBB for disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, schizophrenia and CNS malignancies primarily glioblastomas. Intranasal application offers drug delivery through both direct and indirect pathways for the peripherally administered psychopharmacological agents to CNS. This route could also be exploited for the repurposing of conventional drugs for new therapeutic uses. The limited clinical translation of intranasal formulations has been primarily due to existence of barriers of mucociliary clearance in the nasal cavity, enzyme degradation and low permeability of the nasal epithelium. The present review literature aims to decipher the new paradigms of nano therapeutic systems employed for specific N2B drug delivery of CNS drugs through in silico complexation studies using rationally chosen mucoadhesive polymers (exhibiting unique physicochemical properties of nanocarrier's i.e. surface modification, prolonging retention time in the nasal cavity, improving penetration ability, and promoting brain specific delivery with biorecognitive ligands) via molecular docking simulations. Further, the review intends to delineate the feats and fallacies associated with N2B delivery approaches by understanding the physiological/anatomical considerations via decoding the intranasal drug delivery pathways or critical factors such as rationale and mechanism of excipients, affecting the permeability of CNS drugs through nasal mucosa as well as better efficacy in terms of brain targeting, brain bioavailability and time to reach the brain. Additionally, extensive emphasis has also been laid on the innovative formulations under preclinical investigation along with their assessment by means of in vitro /ex vivo/in vivo N2B models and current characterization techniques predisposing an efficient intranasal delivery of therapeutics. A critical appraisal of novel technologies, intranasal products or medical devices available commercially has also been presented. Finally, it could be warranted that more reminiscent pharmacokinetic/pharmacodynamic relationships or validated computational models are mandated to obtain effective screening of molecular architecture of drug-polymer-mucin complexes for clinical translation of N2B therapeutic systems from bench to bedside.

Effects of Acute Visual Stimulation Exercise on Attention Processes: An ERP Study.

BACKGROUNDS: It remains to be determined whether visual stimuli during exercise differentially influence the attention process. The purpose of the present study was to examine if different color stimuli during aerobic exercise are associated with different attention processes. METHODS: 22 college students completed a four 30-min running session during the presentation of different color stimuli (blue, green, red, and yellow) and without color stimulus on separate visits. The Kanizsa triangle task was administrated before and immediately after exercise to assess the attention process. Behavioral performance (accuracy and response time (RT)) and event-related potential (P2, N2b and P3a) were recorded during the test. RESULTS: Valid/invalid cue RT during the Kaniza test performance was significantly faster following the presentation of color stimuli during treadmill exercise compared to the seated rest. During exercise, these changes were larger after green and yellow stimuli than red in invalid cue RT. P2, N2b and P3a amplitudes of green were significantly larger than the other colors for both valid and invalid cues. Red color showed the lowest P2 and P3a amplitudes for both valid and invalid cues among colors. CONCLUSION: The distinctive neurocognitive changes during aerobic exercise suggest different effects of color stimuli on visual search attention, attention capture, attentional orienting and processing speed. This study will be a first step to understand the optimal environmental setting during exercise for subsequent improvements in the attention process.

Altered Visuospatial Processing in Schizophrenia: An Event-related Potential Microstate Analysis Comparing Patients with and without Hallucinations with Healthy Controls.

Patients with schizophrenia present with various symptoms related to different domains. Abnormalities of auditory and visual perception are parts of a more general problem. Nevertheless, the relationship between the lifetime history of auditory verbal hallucination (AVH), one of the most prevalent symptoms in schizophrenia, and visuospatial deficits remains unclear. This study aimed to investigate differences in hemispheric involvement and visuospatial processing between healthy controls (HCs) and schizophrenia patients with and without AVHs. HCs (N = 20), schizophrenia patients with AVH (AVH group, N = 16), and schizophrenia patients without hallucinations (NH group, N = 10) participated in a 4-choice reaction task with lateralized stimuli. An event-related potential (ERP)-microstate approach was used to analyze ERP differences between the conditions and groups. The schizophrenia patients without hallucinations had slower responses than the HCs. An early visual N1 contralateral to stimulation side was prominent in all groups of participants but with decreased amplitude in the patients with schizophrenia, especially in the AVH group over the right hemisphere. The amplitude of P3b, a cognitive evaluation component, was also decreased in schizophrenia. Compared to AVH and HC groups, the patients in the NH group had altered microstate patterns: P3b was replaced by a novelty component, P3a. Although the difference between both patient groups was only based on the presence of AVHs, our findings indicated that patients had specific visuospatial deficits associated with a lifetime history of hallucinations: patients with AVHs showed early visual component alterations in the right hemisphere, and those without AVHs had more prominent visuospatial impairment.

An optimized method for neuronal differentiation of embryonic stem cells in vitro.

BACKGROUND: Neural differentiation from embryonic stem cells (ESCs) is an excellent model for elucidating the key mechanisms involved in neurogenesis, and also provides an unlimited source of progenitors for cell-based nerve regeneration. However, the existing protocols such as small molecule substances, 3D matrix, co-culture technique and transgenic method, are complicated and difficult to operate, thus are limited by laboratory conditions. Looking for an easy-to-operate protocol with easily gained material and high induction efficiency has always been a hot issue in neuroscience research. NEW METHODS: This paper established an optimized method for embryonic neurogenesis using a strategy of "combinatorial screening". In our study, the whole process of embryonic neurogenesis was divided into two phases, and the differentiation efficiency of seven experimental protocols in phase I and three protocols in phase II were systematically evaluated in A2lox and 129 ESCs. RESULTS: In phase I differentiation, "2-day embryoid bodies formation + 6-day retinoic acid induction" (Phase I-protocol 3) could effectively induce the differentiation of ESCs into neural precursor cells (NPCs). Furthermore, in phase II, N2B27 medium II (Phase II-protocol 3) could better support the subsequent differentiation from NPCs into neurons. COMPARISON WITH EXISTING METHOD(S): Such a combinational method (phase I-protocol 3 and phase II-protocol 3) can realize embryonic neurogenesis with high efficiency, easy implementation and low-cost, and is suitable for promotion in most laboratories. CONCLUSIONS: Through "combinatorial screening" strategy, we established an optimized method for embryonic neurogenesis in vitro, which is expected to be a powerful tool for neuroscience research.

Implicit learning seems to come naturally for children with autism, but not for children with specific language impairment: Evidence from behavioral and ERP data.

Autism spectrum disorder (ASD) and specific language impairment (SLI) are two neurodevelopmental disorders characterized by deficits in verbal and nonverbal communication skills. These skills are thought to develop largely through implicit-or automatic-learning mechanisms. The aim of the current paper was to investigate the role of implicit learning abilities in the atypical development of communication skills in ASD and SLI. In the current study, we investigated Response Times (RTs) and Event Related Potentials (ERPs) during implicit learning on a Serial Reaction Time (SRT) task in a group of typically developing (TD) children (n = 17), a group of autistic children (n = 16), and a group of children with SLI (n = 13). Findings suggest that learning in both ASD and SLI are similar to that in TD. However, electrophysiological findings suggest that autistic children seem to rely mainly on more automatic processes (as reflected by an N2b component), whereas the children with SLI seem to rely on more controlled processes (as reflected by a P3 component). The TD children appear to use a combination of both learning mechanisms. These findings suggest that clinical interventions should aim at compensating for an implicit learning deficit in children with SLI, but not in children with ASD. Future research should focus on developmental differences in implicit learning and related neural correlates in TD, ASD, and SLI. Autism Res 2018, 11: 1050-1061. © 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: Autism and Specific Language Impairment (SLI) are two disorders characterized by problems in social communication and language. Social communication and language are believed to be learned in an automatic way. This is called "implicit learning." We have found that implicit learning is intact in autism. However, in SLI there seems different brain activity during implicit learning. Maybe children with SLI learn differently, and maybe this different learning makes it more difficult for them to learn language.

Background Suppression and its Relation to Foreground Processing of Speech Versus Non-speech Streams.

Since sound perception takes place against a background with a certain amount of noise, both speech and non-speech processing involve extraction of target signals and suppression of background noise. Previous works on early processing of speech phonemes largely neglected how background noise is encoded and suppressed. This study aimed to fill in this gap. We adopted an oddball paradigm where speech (vowels) or non-speech stimuli (complex tones) were presented with or without a background of amplitude-modulated noise and analyzed cortical responses related to foreground stimulus processing, including mismatch negativity (MMN), N2b, and P300, as well as neural representations of the background noise, that is, auditory steady-state response (ASSR). We found that speech deviants elicited later and weaker MMN, later N2b, and later P300 than non-speech ones, but N2b and P300 had similar strength, suggesting more complex processing of certain acoustic features in speech. Only for vowels, background noise enhanced N2b strength relative to silence, suggesting an attention-related speech-specific process to improve perception of foreground targets. In addition, noise suppression in speech contexts, quantified by ASSR amplitude reduction after stimulus onset, was lateralized towards the left hemisphere. The left-lateralized suppression following N2b was associated with the N2b enhancement in noise for speech, indicating that foreground processing may interact with background suppression, particularly during speech processing. Together, our findings indicate that the differences between perception of speech and non-speech sounds involve not only the processing of target information in the foreground but also the suppression of irrelevant aspects in the background.

Alterations in Titin Properties and Myocardial Fibrosis Correlate With Clinical Phenotypes in Hemodynamic Subgroups of Severe Aortic Stenosis.

Titin-isoform expression, titin phosphorylation, and myocardial fibrosis were studied in 30 patients with severe symptomatic aortic stenosis (AS). Patients were grouped into "classical" high-gradient, normal-flow AS with preserved ejection fraction (EF); "paradoxical" low-flow, low-gradient AS with preserved EF; and AS with reduced EF. Nonfailing donor hearts served as controls. AS was associated with increased fibrosis, titin-isoform switch toward compliant N2BA, and both total and site-specific titin hypophosphorylation compared with control hearts. All AS subtypes revealed titin and matrix alterations. The extent of myocardial remodeling in "paradoxical" AS was no less severe than in other AS subtypes, thus explaining the unfavorable prognosis.

Autism: Too eager to learn? Event related potential findings of increased dependency on intentional learning in a serial reaction time task.

It has been suggested that people with autism spectrum disorder (ASD) have an increased tendency to use explicit (or intentional) learning strategies. This altered learning may play a role in the development of the social communication difficulties characterizing ASD. In the current study, we investigated incidental and intentional sequence learning using a Serial Reaction Time (SRT) task in an adult ASD population. Response times and event related potentials (ERP) components (N2b and P3) were assessed as indicators of learning and knowledge. Findings showed that behaviorally, sequence learning and ensuing explicit knowledge were similar in ASD and typically developing (TD) controls. However, ERP findings showed that learning in the TD group was characterized by an enhanced N2b, while learning in the ASD group was characterized by an enhanced P3. These findings suggest that learning in the TD group might be more incidental in nature, whereas learning in the ASD group is more intentional or effortful. Increased intentional learning might serve as a strategy for individuals with ASD to control an overwhelming environment. Although this led to similar behavioral performances on the SRT task, it is very plausible that this intentional learning has adverse effects in more complex social situations, and hence contributes to the social impairments found in ASD. Autism Res 2017, 10: 1533-1543. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Facilitation dynamics of late somatosensory evoked potentials after sural nerve stimulation.

OBJECTIVE: Somatosensory evoked potentials (SSEPs) could be suitable for elucidating the properties of synaptic potentials (SPs). Two experiments were designed for this purpose. METHODS: 1st experiment: the sural nerve was stimulated in 13 subjects with single or trains of 3 stimuli (1Hz or 0.4Hz), the within train interstimulus interval (ISI) was stepwise extended from 2 to 10ms. Cz' against Fz, time interval 500ms. 2nd experiment: Gating was investigated in a paired stimulus paradigm with intervals of 0.7, 1, 2, 5s in 15 subjects after single and train stimuli (ISI 3ms) with equal stimulus and recording positions. RESULTS: 1st experiment: N1-P1, P1-N2a, and P2-N2b but not N37-P40 displayed a significant gain in amplitude following train stimuli compared with single stimuli. Significantly larger N1-P1 amplitude values were observed with 0.4Hz stimulus repetition compared with 1.0Hz. Short ISIs of 2-4ms led to higher N1-P1 amplitudes than obtained with longer ISIs of 7-10ms. 2nd experiment: recovery of the habituated N1-P1 amplitude was complete when the 2nd of 2 stimuli followed after 2s. CONCLUSIONS: SSEP vertex potential amplitudes (especially N1-P1) recorded after train stimuli presumably reflect the decay dynamics of excitatory postsynaptic potentials. Recovery of the habituated N1 (2nd experiment) was complete within 2s. SIGNIFICANCE: Our study may be relevant to study properties of excitatory synaptic potentials in diseases of the central nervous system such as e.g. epilepsy or migraine.