Characteristics of the transverse 2D uniserial arrangement of rows of decussating enamel rods in the inner enamel layer of mouse mandibular incisors

The 2D arrangement of rows of enamel rods with alternating (decussating) tilt angles across the thickness of the inner layer in rat and mouse incisor enamel is well known and assumed to occur in a uniform and repetitive pattern. Some irregularities in the arrangement of rows have been reported, but no detailed investigation of row structure across the entire inner enamel layer currently exists. This investigation was undertaken to determine if the global row pattern in mouse mandibular incisor enamel is predominately regular in nature with only occasional anomalies or if rows of enamel rods have more spatial complexity than previously suspected. The data from this investigation indicate that rows of enamel rods are highly variable in length and have complex transverse arrangements across the width and thickness of the inner enamel layer. The majority of rows are short or medium in length, with 87% having < 100 rods per row. The remaining 13% are long rows (with 100-233 rods per row) that contain 46% of all enamel rods seen in transverse sections. Variable numbers of rows were associated with the lateral, central and mesial regions of the enamel layer. Each region contained different ratios of short, medium and long rows. A variety of relationships was found along the transverse length of rows in each region, including uniform associations of alternating rod tilts between neighboring rows, and instances where two rows having the same rod tilt were paired for variable distances then moved apart to accommodate rows of opposite tilt. Sometimes a row appeared to branch into two rows with the same tilt, or conversely where two rows merged into one row depending upon the mesial-to-lateral direction in which the row was viewed. Some rows showed both pairing and branching/merging along their length. These tended to be among the longest rows identified, and they often crossed the central region with extensions into the lateral and mesial regions. The most frequent row arrangement was a row of petite length nestled at the side of another row having the same rod tilt (30% of all rows). These were termed -focal stacks- and may relate to the evolution of uniserial rat and mouse incisor enamel from a multilayered ancestor. The mesial and lateral endpoints of rows also showed complex arrangements with the dentinoenamel junction (DEJ), the inner enamel layer itself, and the boundary area to the outer enamel layer. It was concluded that the diversity in row lengths and various spatial arrangements both within and between rows across the transverse plane provides a method to interlock the enamel layer across each region and keep the enamel layer compact relative to the curving DEJ surface. The uniserial pattern for rows in mouse mandibular incisors is not uniform, but diverse and very complex.Enamel rods in rodent incisors are arranged as stacked rows with alternating tilt angles across the transverse plane of the tooth. This study quantifies row patterns to determine if the layering of the rows and the alternating tilt angles are uniform or more irregular and complex in arrangement. The results indicated considerable diversity in row lengths, row tilts and 2D spatial row arrangements both within and between rows.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151964/1/joa13053_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151964/2/joa13053.pd

From exercise intolerance to functional improvement: The second wind phenomenon in the identification of McArdle disease

McArdle disease is the most common of the glycogen storage diseases. Onset of symptoms is usually in childhood with muscle pain and restricted exercise capacity. Signs and symptoms are often ignored in children or put down to 'growing pains' and thus diagnosis is often delayed. Misdiagnosis is not uncommon because several other conditions such as muscular dystrophy and muscle channelopathies can manifest with similar symptoms. A simple exercise test performed in the clinic can however help to identify patients by revealing the second wind phenomenon which is pathognomonic of the condition. Here a patient is reported illustrating the value of using a simple 12 minute walk test.RSS is funded by Ciências sem Fronteiras/CAPES Foundation. The authors would like to thank the Association for Glycogen Storage Disease (UK), the EUROMAC Registry funded by the European Union, the Muscular Dystrophy Campaign, the NHS National Specialist Commissioning Group and the Myositis Support Group for funding

Tropomyosin Tpm3.1 is required to maintain the structure and function of the axon initial segment

The axon initial segment (AIS) is the site of action potential initiation and serves as a cargo transport filter and diffusion barrier that helps maintain neuronal polarity. The AIS actin cytoskeleton comprises actin patches and periodic sub-membranous actin rings. We demonstrate that tropomyosin isoform Tpm3.1 co-localizes with actin patches and that the inhibition of Tpm3.1 led to a reduction in the density of actin patches. Furthermore, Tpm3.1 showed a periodic distribution similar to sub-membranous actin rings but Tpm3.1 was only partially congruent with sub-membranous actin rings. Nevertheless, the inhibition of Tpm3.1 affected the uniformity of the periodicity of actin rings. Furthermore, Tpm3.1 inhibition led to reduced accumulation of AIS structural and functional proteins, disruption in sorting somatodendritic and axonal proteins, and a reduction in firing frequency. These results show that Tpm3.1 is necessary for the structural and functional maintenance of the AIS.Peer reviewe

Estimation of biological heart age using cardiovascular magnetic resonance radiomics

We developed a novel interpretable biological heart age estimation model using cardiovascular magnetic resonance radiomics measures of ventricular shape and myocardial character. We included 29,996 UK Biobank participants without cardiovascular disease. Images were segmented using an automated analysis pipeline. We extracted 254 radiomics features from the left ventricle, right ventricle, and myocardium of each study. We then used Bayesian ridge regression with tenfold cross-validation to develop a heart age estimation model using the radiomics features as the model input and chronological age as the model output. We examined associations of radiomics features with heart age in men and women, observing sex-diferential patterns. We subtracted actual age from model estimated heart age to calculate a “heart age delta”, which we considered as a measure of heart aging. We performed a phenome-wide association study of 701 exposures with heart age delta. The strongest correlates of heart aging were measures of obesity, adverse serum lipid markers, hypertension, diabetes, heart rate, income, multimorbidity, musculoskeletal health, and respiratory health. This technique provides a new method for phenotypic assessment relating to cardiovascular aging; further studies are required to assess whether it provides incremental risk information over current approaches

Re-Evaluation of Sinocastor (Rodentia: Castoridae) with Implications on the Origin of Modern Beavers

The extant beaver, Castor, has played an important role shaping landscapes and ecosystems in Eurasia and North America, yet the origins and early evolution of this lineage remain poorly understood. Here we use a geometric morphometric approach to help re-evaluate the phylogenetic affinities of a fossil skull from the Late Miocene of China. This specimen was originally considered Sinocastor, and later transferred to Castor. The aim of this study was to determine whether this form is an early member of Castor, or if it represents a lineage outside of Castor. The specimen was compared to 38 specimens of modern Castor (both C. canadensis and C. fiber) as well as fossil specimens of C. fiber (Pleistocene), C. californicus (Pliocene) and the early castorids Steneofiber eseri (early Miocene). The results show that the specimen falls outside the Castor morphospace and that compared to Castor, Sinocastor possesses a: 1) narrower post-orbital constriction, 2) anteroposteriorly shortened basioccipital depression, 3) shortened incisive foramen, 4) more posteriorly located palatine foramen, 5) longer rostrum, and 6) longer braincase. Also the specimen shows a much shallower basiocciptal depression than what is seen in living Castor, as well as prominently rooted molars. We conclude that Sinocastor is a valid genus. Given the prevalence of apparently primitive traits, Sinocastor might be a near relative of the lineage that gave rise to Castor, implying a possible Asiatic origin for Castor

Ongoing developments in sporadic inclusion body myositis

Sporadic inclusion body myositis (IBM) is an acquired muscle disorder associated with ageing, for which there is no effective treatment. Ongoing developments include: genetic studies that may provide insights regarding the pathogenesis of IBM, improved histopathological markers, the description of a new IBM autoantibody, scrutiny of the diagnostic utility of clinical features and biomarkers, the refinement of diagnostic criteria, the emerging use of MRI as a diagnostic and monitoring tool, and new pathogenic insights that have led to novel therapeutic approaches being trialled for IBM, including treatments with the objective of restoring protein homeostasis and myostatin blockers. The effect of exercise in IBM continues to be investigated. However, despite these ongoing developments, the aetiopathogenesis of IBM remains uncertain. A translational and multidisciplinary collaborative approach is critical to improve the diagnosis, treatment, and care of patients with IBM

PathFinder: mining signal transduction pathway segments from protein-protein interaction networks

<p>Abstract</p> <p>Background</p> <p>A Signal transduction pathway is the chain of processes by which a cell converts an extracellular signal into a response. In most unicellular organisms, the number of signal transduction pathways influences the number of ways the cell can react and respond to the environment. Discovering signal transduction pathways is an arduous problem, even with the use of systematic genomic, proteomic and metabolomic technologies. These techniques lead to an enormous amount of data and how to interpret and process this data becomes a challenging computational problem.</p> <p>Results</p> <p>In this study we present a new framework for identifying signaling pathways in protein-protein interaction networks. Our goal is to find biologically significant pathway segments in a given interaction network. Currently, protein-protein interaction data has excessive amount of noise, e.g., false positive and false negative interactions. First, we eliminate false positives in the protein-protein interaction network by integrating the network with microarray expression profiles, protein subcellular localization and sequence information. In addition, protein families are used to repair false negative interactions. Then the characteristics of known signal transduction pathways and their functional annotations are extracted in the form of association rules.</p> <p>Conclusion</p> <p>Given a pair of starting and ending proteins, our methodology returns candidate pathway segments between these two proteins with possible missing links (recovered false negatives). In our study, <it>S. cerevisiae </it>(yeast) data is used to demonstrate the effectiveness of our method.</p

Organization of Physical Interactomes as Uncovered by Network Schemas

Large-scale protein-protein interaction networks provide new opportunities for understanding cellular organization and functioning. We introduce network schemas to elucidate shared mechanisms within interactomes. Network schemas specify descriptions of proteins and the topology of interactions among them. We develop algorithms for systematically uncovering recurring, over-represented schemas in physical interaction networks. We apply our methods to the S. cerevisiae interactome, focusing on schemas consisting of proteins described via sequence motifs and molecular function annotations and interacting with one another in one of four basic network topologies. We identify hundreds of recurring and over-represented network schemas of various complexity, and demonstrate via graph-theoretic representations how more complex schemas are organized in terms of their lower-order constituents. The uncovered schemas span a wide range of cellular activities, with many signaling and transport related higher-order schemas. We establish the functional importance of the schemas by showing that they correspond to functionally cohesive sets of proteins, are enriched in the frequency with which they have instances in the H. sapiens interactome, and are useful for predicting protein function. Our findings suggest that network schemas are a powerful paradigm for organizing, interrogating, and annotating cellular networks