State-dependencies of learning across brain scales

Learning is a complex brain function operating on different time scales, from milliseconds to years, which induces enduring changes in brain dynamics. The brain also undergoes continuous “spontaneous” shifts in states, which, amongst others, are characterized by rhythmic activity of various frequencies. Besides the most obvious distinct modes of waking and sleep, wake-associated brain states comprise modulations of vigilance and attention. Recent findings show that certain brain states, particularly during sleep, are essential for learning and memory consolidation. Oscillatory activity plays a crucial role on several spatial scales, for example in plasticity at a synaptic level or in communication across brain areas. However, the underlying mechanisms and computational rules linking brain states and rhythms to learning, though relevant for our understanding of brain function and therapeutic approaches in brain disease, have not yet been elucidated. Here we review known mechanisms of how brain states mediate and modulate learning by their characteristic rhythmic signatures. To understand the critical interplay between brain states, brain rhythms, and learning processes, a wide range of experimental and theoretical work in animal models and human subjects from the single synapse to the large-scale cortical level needs to be integrated. By discussing results from experiments and theoretical approaches, we illuminate new avenues for utilizing neuronal learning mechanisms in developing tools and therapies, e.g., for stroke patients and to devise memory enhancement strategies for the elderly

Air–Liquid Interface In Vitro Models for Respiratory Toxicology Research: Consensus Workshop and Recommendations

In vitro air–liquid interface (ALI) cell culture models can potentially be used to assess inhalation toxicology endpoints and are usually considered, in terms of relevancy, between classic (i.e., submerged) in vitro models and animal-based models. In some situations that need to be clearly defined, ALI methods may represent a complement or an alternative option to in vivo experimentations or classic in vitro methods. However, it is clear that many different approaches exist and that only very limited validation studies have been carried out to date. This means comparison of data from different methods is difficult and available methods are currently not suitable for use in regulatory assessments. This is despite inhalation toxicology being a priority area for many governmental organizations. In this setting, a 1-day workshop on ALI in vitro models for respiratory toxicology research was organized in Paris in March 2016 to assess the situation and to discuss what might be possible in terms of validation studies. The workshop was attended by major parties in Europe and brought together more than 60 representatives from various academic, commercial, and regulatory organizations. Following plenary, oral, and poster presentations, an expert panel was convened to lead a discussion on possible approaches to validation studies for ALI inhalation models. A series of recommendations were made and the outcomes of the workshop are reported

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Macular maldevelopment in ATF6-mediated retinal dysfunction

10.1080/13816810.2019.1706749Ophthalmic Genetics406564-56

A Reproducible Papain-Induced Disk Degeneration Model of Reduced GAG and Hydration

Introduction Nucleus pulposus (NP) digestion using chymopapain is a clinical procedure to release pressure of a herniated disk. It reduces matrix content and hence offers a method to simulate a condition of disk degeneration with reduced glycosaminoglycans (GAG) and water content.1 The aims of the study is to characterize a set of in vitro disk degeneration model (DDM) of different severity of GAG and water loss by using various concentration of papain and second to determine the initial response of mesenchymal stem cells (MSC) introduced in these papain-induced DDM. Materials and Methods Disk Degeneration Model. Bovine caudal IVDs (diameter 16 to 22 mm) with endplates were isolated as previously described which is readily for in vitro culture in a multiloading bioreactor.2 Various concentration of papain (3, 15, 30, 60, 150 U/mL, n = 4 for each group) (Sigma-Aldrich, Switzerland) or phosphate buffer saline (PBS control) were injected into the center of the disk using a 25 G. Ten days after the injection of papain, cell viability was assessed by staining the tissue with Live/Dead stain (Fluka, Sigma-Aldrich, Switzerland) and visualized by confocal microscopy.3 The other half of the tissue was evaluated by histology for overall matrix organization. Nondecalcified tissues were embedded in methylmethacrylate (MMA) for histology sectioning. Overall matrix composition was evaluated by staining the 6 µm section with safranin O and fast green, and hematoxylin and eosin. Disk hydration of the bovine tail disk injected with papain and PBS after 2 days was assessed by magnetic resonance imaging (MRI) using T2* protocol. MSC Injection. Human MSCs were isolated from bone marrow obtained from spinal surgery. MSC were labeled with a fluorescence cell membrane tracker DiO (Invitrogen, Basel, Switzerland) and then suspended in culture medium and injected into the nucleus of the DDM (30 U/mL) or a PBS control disk. MSC distribution and viability were evaluated after 2 days of free swelling culture by staining the tissue with DAPI and calcein AM and imaging with confocal microscopy. The presence of live injected cells were visualized as colocalization of orange DiL dye and calcein AM live cell stain. Results Disk Degeneration Model. Cell viability of the papain-digested NP was maintained at ∼75% after 10 days in all the injected papain concentration. In the mild DDM (3 U/mL), small amount of GAG was maintained in the center of the disk. In the medium DDM (30 to 60 U/mL), GAG was completely lost in the entire disk with a small cavity in the center while AF maintained intact. In the DDM (150 U/mL), GAG was completely lost in the entire disk with a large cavity present in the center of the disk and the AF was collapsed. MRI result showed that there was a mild decrease in disk hydration by injecting 3 U/mL papain, and half of the disk hydration was lost when injecting 150 U/mL papain. ( Fig. 1 ) MSC Injection. At day 2, MSC injected into a control disk (injected with PBS) formed a cluster and largely decreased the MSC viability. While MSC injected in the DDM dispread inside the NP and a significantly higher cell viability was resulted when MSC were injected into this papain-induced DDM (40.64 ± 10.81%) than in the PBS control (14.50 ± 6.08%) ( n = 4, p = 0.0329). [Figure: see text] Conclusion A reproducible DDM of various severities of reduced GAG and hydration can be achieved by injecting various dosage of papain without compromising the disk cell viability. This model is ready for the testing of injectable tissue engineering strategies inside a controlled loading and culture environment of a bioreactor. MSCs injected as cell suspension have a poor-chance of survival in a healthy or degenerated disk. This indicated that matrix content of the disk affect the initial survival of the introduced cells and revealed that the use of cell carrier/scaffold will be needed for cell therapy. Acknowledgements This project was supported by the Swiss National Science Foundation (SNF # 310030–127586/1). I confirm having declared any potential conflict of interest for all authors listed on this abstract Yes Disclosure of Interest None declared Roberts et al. BMC Musculoskelet Disord 2008;9:24 Chan S et al. JoVE, In press, 2011 Gantenbein-Ritter B et al. Tissue Engineering Part C 2008;14:353–358 </jats:sec

Evaluation of mechanical properties of five cements for orthodontic band cementation

The aim of this in vitro study was to compare the flexural, compressive and diametral tensile strengths of five cements used in orthodontics for band cementation. Twelve specimens of each cement were tested: 1 - GC Fuji Ortho Band (FJ), GC America Inc.; 2 - Meron (MR), Voco; 3 - Multi-Cure Glass Ionomer Band Cement (MC), 3M Unitek; 4 - Band-Lok (BL), Reliance Orthodontic Products; and 5 - Ketac Cem (KC), 3M ESPE. The results (mean) for diametral tensile strength were: 10.51 MPa (FJ), 9.60 MPa (MR), 20.04 MPa (MC), 42.80 MPa (BL), and 4.08 MPa (KC). The results for compressive strength were (in the same order): 64.50 MPa, 77.71 MPa, 94.21 MPa, 193.88 MPa, and 81.93 MPa. The results for flexural strength were (in the same order): 20.72 MPa, 25.84 MPa, 53.41 MPa, 137.41 MPa, and 20.50 MPa. The statistical analysis was performed by two-way ANOVA and Tukey tests with p-value &#163; 0.05. In terms of diametral tensile strength, BL showed the highest strength statistically, and MC, the second highest. In terms of compressive tensile strength, BL showed the highest strength statistically, and FJ did not attain the minimum recommended strength. In terms of flexural tensile strength, BL cement was superior to MC, and MR, FJ and KC were equivalent and inferior to BL and MC