3-D neurohistology of transparent tongue in health and injury with optical clearing

Tongue receives extensive innervation to perform taste, sensory, and motor functions. Details of the tongue neuroanatomy and its plasticity in response to injury offer insights to investigate tongue neurophysiology and pathophysiology. However, due to the dispersed nature of the neural network, standard histology cannot provide a global view of the innervation. We prepared transparent mouse tongue by optical clearing to reveal the spatial features of the tongue innervation and its remodeling in injury. Immunostaining of neuronal markers, including PGP9.5 (pan-neuronal marker), calcitonin gene-related peptide (sensory nerves), tyrosine hydroxylase (sympathetic nerves), and vesicular acetylcholine transporter (cholinergic parasympathetic nerves and neuromuscular junctions), was combined with vessel painting and nuclear staining to label the tissue network and architecture. The tongue specimens were immersed in the optical-clearing solution to facilitate photon penetration for 3-dimensiontal (3-D) confocal microscopy. Taking advantage of the transparent tissue, we simultaneously revealed the tongue microstructure and innervation with subcellular-level resolution. 3-D projection of the papillary neurovascular complex and taste bud innervation was used to demonstrate the spatial features of tongue mucosa and the panoramic imaging approach. In the tongue injury induced by 4-nitroquinoline 1-oxide administration in the drinking water, we observed neural tissue remodeling in response to the changes of mucosal and muscular structures. Neural networks and the neuromuscular junctions were both found rearranged at the peri-lesional region, suggesting the nerve-lesion interactions in response to injury. Overall, this new tongue histological approach provides a useful tool for 3-D imaging of neural tissues to better characterize their roles with the mucosal and muscular components in health and disease

Canadian Multidisciplinary Core Curriculum for Musculoskeletal Health

ABSTRACT. Objective. To determine the level of agreement among the Bone and Joint Decade Undergraduate Curriculum Group (BJDUCG) core curriculum recommendations for musculoskeletal (MSK) conditions targeted for undergraduate medical education and what the physicians and surgeons of Canada thought to be important at the postgraduate level of education. Methods. An 80-item questionnaire was developed. A cross-sectional survey of educators representing 77 Canadian accredited academic programs representing 6 disciplines in medicine that manage patients with MSK conditions was completed. Histograms, Kruskal-Wallis, and principal component analyses were computed. Results. In total, 164/175 (94%) respondents participated in the study. All 80 curriculum items received a mean score of at least 3.0/4.0. Sixty-four out of 80 items were ranked to be at least 3.5/4.0, and 35 items were ranked to be at least 3.8/4.0, suggesting that these items may be core content for all disciplines. Conclusion. The World Health Organization declared the years 2000 to 2010 as The Bone and Joint Decade. The main goal is to improve the quality of life for people with MSK disorders worldwide. One aim of the BJD is to increase education of healthcare providers at all levels. The BJDUCG established a set of core curriculum recommendations for MSK conditions. Our study gives reliable statistical evidence of agreement among what the BJDUCG recommended for an MSK core curriculum for medical schools and what the physicians and surgeons of Canada thought to be important for residency education in several disciplines

14-3-3σ Regulates β-Catenin-Mediated Mouse Embryonic Stem Cell Proliferation by Sequestering GSK-3β

[[abstract]]Background: Pluripotent embryonic stem cells are considered to be an unlimited cell source for tissue regeneration and cell-based therapy. Investigating the molecular mechanism underlying the regulation of embryonic stem cell expansion is thus important. 14-3-3 proteins are implicated in controlling cell division, signaling transduction and survival by interacting with various regulatory proteins. However, the function of 14-3-3 in embryonic stem cell proliferation remains unclear. Methodology and Principal Findings: In this study, we show that all seven 14-3-3 isoforms were detected in mouse embryonic stem cells. Retinoid acid suppressed selectively the expression of 14-3-3σ isoform. Knockdown of 14-3-3σ with siRNA reduced embryonic stem cell proliferation, while only 14-3-3σ transfection increased cell growth and partially rescued retinoid acid-induced growth arrest. Since the growth-enhancing action of 14-3-3σ was abrogated by β-catenin knockdown, we investigated the influence of 14-3-3σ overexpression on β-catenin/GSK-3β. 14-3-3σ bound GSK-3β and increased GSK-3β phosphorylation in a PI-3K/Akt-dependent manner. It disrupted β-catenin binding by the multiprotein destruction complex. 14-3-3σ overexpression attenuated β-catenin phosphorylation and rescued the decline of β-catenin induced by retinoid acid. Furthermore, 14-3-3σ enhanced Wnt3a-induced β-catenin level and GSK-3β phosphorylation. DKK, an inhibitor of Wnt signaling, abolished Wnt3a-induced effect but did not interfere GSK-3β/14-3-3σ binding. Significance:Our findings show for the first time that 14-3-3σ plays an important role in regulating mouse embryonic stem cell proliferation by binding and sequestering phosphorylated GSK-3β and enhancing Wnt-signaled GSK-3β inactivation. 14-3-3σ is a novel target for embryonic stem cell expansion

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

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

The best EBLUP in the Fay–Herriot model

Empirical best linear unbiased prediction, Mean squared error, Small area estimation, Third-order approximation,

Detection of MET Gene Copy Number in Cancer Samples Using the Droplet Digital PCR Method.

The analysis of MET gene copy number (CN) has been considered to be a potential biomarker to predict the response to MET-targeted therapies in various cancers. However, the current standard methods to determine MET CN are SNP 6.0 in the genomic DNA of cancer cell lines and fluorescence in situ hybridization (FISH) in tumor models, respectively, which are costly and require advanced technical skills and result in relatively subjective judgments. Therefore, we employed a novel method, droplet digital PCR (ddPCR), to determine the MET gene copy number with high accuracy and precision.The genomic DNA of cancer cell lines or tumor models were tested and compared with the MET gene CN and MET/CEN-7 ratio determined by SNP 6.0 and FISH, respectively.In cell lines, the linear association of the MET CN detected by ddPCR and SNP 6.0 is strong (Pearson correlation = 0.867). In tumor models, the MET CN detected by ddPCR was significantly different between the MET gene amplification and non-amplification groups according to FISH (mean: 15.4 vs 2.1; P = 0.044). Given that MET gene amplification is defined as MET CN >5.5 by ddPCR, the concordance rate between ddPCR and FISH was 98.0%, and Cohen's kappa coefficient was 0.760 (95% CI, 0.498-1.000; P <0.001).The results demonstrated that the ddPCR method has the potential to quantify the MET gene copy number with high precision and accuracy as compared with the results from SNP 6.0 and FISH in cancer cell lines and tumor samples, respectively

Measurement of <i>MET</i> copy number in PDX models using ddPCR versus FISH.

<p>The data is based on a linear regression model that adjusts for FISH ratio with intercept. Solid line indicates fitting curve; gray box represents 95% confidence limits; dashed line depicts 95% prediction limits. Each data for <i>MET</i> CN using ddPCR represents two or three merged technical replicate wells with no template control (NTC) as a negative control.</p

Measurement of <i>MET</i> copy number in cancer cell lines using ddPCR versus SNP 6.0.

<p>The data is based on a linear regression model that adjusts for SNP 6.0 with intercept. Solid line indicates fitting curve; gray box represents 95% confidence limits; dashed line depicts 95% prediction limits. Each data for <i>MET</i> CN using ddPCR represents two or three merged technical replicate wells with no template control (NTC) as a negative control.</p