Dual Chromatin and Cytoskeletal Remodeling by SETD2

Posttranslational modifications (PTMs) of tubulin specify microtubules for specialized cellular functions and comprise what is termed a "tubulin code." PTMs of histones comprise an analogous "histone code," although the "readers, writers, and erasers" of the cytoskeleton and epigenome have heretofore been distinct. We show that methylation is a PTM of dynamic microtubules and that the histone methyltransferase SET-domain-containing 2 (SETD2), which is responsible for H3 lysine 36 trimethylation (H3K36me3) of histones, also methylates α-tubulin at lysine 40, the same lysine that is marked by acetylation on microtubules. Methylation of microtubules occurs during mitosis and cytokinesis and can be ablated by SETD2 deletion, which causes mitotic spindle and cytokinesis defects, micronuclei, and polyploidy. These data now identify SETD2 as a dual-function methyltransferase for both chromatin and the cytoskeleton and show a requirement for methylation in maintenance of genomic stability and the integrity of both the tubulin and histone codes

A deterministic oscillatory model of microtubule growth and shrinkage for differential actions of short chain fatty acids.

Short chain fatty acids (SCFA), principally acetate, propionate, butyrate and valerate, are produced in pharmacologically relevant concentrations by the gut microbiome. Investigations indicate that they exert beneficial effects on colon epithelia. There is increasing interest in whether different SCFAs have distinct functions which may be exploited for prevention or treatment of colonic diseases including colorectal cancer (CRC), inflammatory bowel disease and obesity. Based on experimental evidence, we hypothesised that odd-chain SCFAs may possess anti-mitotic capabilities in colon cancer cells by disrupting microtubule (MT) structural integrity via dysregulation of β-tubulin isotypes. MT dynamic instability is an essential characteristic of MT cellular activity. We report a minimal deterministic model that takes a novel approach to explore the hypothesised pathway by triggering spontaneous oscillations to represent MT dynamic behaviour. The dynamicity parameters in silico were compared to those reported in vitro. Simulations of untreated and butyrate (even-chain length) treated cells reflected MT behaviour in interphase or untreated control cells. The propionate and valerate (odd-chain length) simulations displayed increased catastrophe frequencies and longer periods of MT-fibre shrinkage. Their enhanced dynamicity was dissimilar to that observed in mitotic cells, but parallel to that induced by MT-destabilisation treatments. Antimicrotubule drugs act through upward or downward modulation of MT dynamic instability. Our computational modelling suggests that metabolic engineering of the microbiome may facilitate managing CRC risk by predicting outcomes of SCFA treatments in combination with AMDs

Reproducibility of goniometric measurement of the knee in the in-hospital phase following total knee arthroplasty

<p>Abstract</p> <p>Background</p> <p>The objective of the present study was to assess interobserver reproducibility (in terms of reliability and agreement) of active and passive measurements of knee RoM using a long arm goniometer, performed by trained physical therapists in a clinical setting in total knee arthroplasty patients, within the first four days after surgery.</p> <p>Methods</p> <p>Test-retest analysis</p> <p>Setting: University hospital departments of orthopaedics and physical therapy</p> <p>Participants: Two experienced physical therapists assessed 30 patients, three days after total knee arthroplasty.</p> <p>Main outcome measure: RoM measurement using a long-arm (50 cm) goniometer</p> <p>Agreement was calculated as the mean difference between observers ± 95% CI of this mean difference. The intraclass correlation coefficient (ICC) was calculated as a measure of reliability, based on two-way random effects analysis of variance.</p> <p>Results</p> <p>The lowest level of agreement was that for measurement of passive flexion with the patient in supine position (mean difference 1.4°; limits of agreement 16.2° to 19° for the difference between the two observers. The highest levels of agreement were found for measurement of passive flexion with the patient in sitting position and for measurement of passive extension (mean difference 2.7°; limits of agreement -6.7 to 12.1 and mean difference 2.2°; limits of agreement -6.2 to 10.6 degrees, respectively). The ability to differentiate between subjects ranged from 0.62 for measurement of passive extension to 0.89 for measurements of active flexion (ICC values).</p> <p>Conclusion</p> <p>Interobserver agreement for flexion as well as extension was only fair. When two different observers assess the same patients in the acute phase after total knee arthroplasty using a long arm goniometer, differences in RoM of less than eight degrees cannot be distinguished from measurement error. Reliability was found to be acceptable for comparison on group level, but poor for individual comparisons over time.</p

Fast Detection of Unexpected Sound Intensity Decrements as Revealed by Human Evoked Potentials

The detection of deviant sounds is a crucial function of the auditory system and is reflected by the automatically elicited mismatch negativity (MMN), an auditory evoked potential at 100 to 250 ms from stimulus onset. It has recently been shown that rarely occurring frequency and location deviants in an oddball paradigm trigger a more negative response than standard sounds at very early latencies in the middle latency response of the human auditory evoked potential. This fast and early ability of the auditory system is corroborated by the finding of neurons in the animal auditory cortex and subcortical structures, which restore their adapted responsiveness to standard sounds, when a rare change in a sound feature occurs. In this study, we investigated whether the detection of intensity deviants is also reflected at shorter latencies than those of the MMN. Auditory evoked potentials in response to click sounds were analyzed regarding the auditory brain stem response, the middle latency response (MLR) and the MMN. Rare stimuli with a lower intensity level than standard stimuli elicited (in addition to an MMN) a more negative potential in the MLR at the transition from the Na to the Pa component at circa 24 ms from stimulus onset. This finding, together with the studies about frequency and location changes, suggests that the early automatic detection of deviant sounds in an oddball paradigm is a general property of the auditory system

The need for harmonization and innovation of neuropsychological assessment in neurodegenerative dementias in Europe: consensus document of the Joint Program for Neurodegenerative Diseases Working Group

Cognitive, behavioural, and functional assessment is crucial in longitudinal studies of neurodegenerative dementias (NDD). Central issues, such as the definition of the study population (asymptomatic, at risk, or individuals with dementia), the detection of change/decline, and the assessment of relevant outcomes depend on quantitative measures of cognitive, behavioural, and functional status. Currently, we are far from having available reliable protocols and tools for the assessment of dementias in Europe. The main problems are the heterogeneity of the tools used across different European countries, the lack of standardisation of administration and scoring methods across centres, and the limited information available about the psychometric properties of many tests currently in widespread use. This situation makes it hard to compare results across studies carried out in different centres, thus hampering research progress, in particular towards the contribution to a “big data” common data set. We present here the results of a project funded by the Joint Program for Neurodegenerative Diseases (JPND) and by the Italian Ministry of Health. The project aimed at providing a consensus framework for the harmonisation of assessment tools to be applied to research in neurodegenerative disorders affecting cognition across Europe. A panel of European experts reviewed the current methods of neuropsychological assessment, identified pending issues, and made recommendations for the harmonisation of neuropsychological assessment of neurodegenerative dementias in Europe. A consensus was achieved on the general recommendations to be followed in developing procedures and tools for neuropsychological assessment, with the aim of harmonising tools and procedures to achieve more reliable data on the cognitive-behavioural examination. The results of this study should be considered as a first step to enhancing a common view and practise on NDD assessment across European countries

Backseat drivers:Cargo adaptors and dynactin activate cytoplasmic dynein motility

Control of the activity of the microtubule motor cytoplasmic dynein 1 is essential for its function in intracellular transport. A recent paper by McKenney et al. published in Science shows that activation of processive dynein motility requires the formation of cargo adaptor-dynein-dynactin complexes

ACKNOWLEDGMENTS CKNOWLEDGMENTS

reviews of the original draft of the manuscript. Lauren Munday, Walt Cooper, Everett Latch, Rick Goldsmith, Darrel Pruett, and Peggy Ushakoff (all WDFW) proved indispensable when preparing and printing the final report. Major funding for this project was made possible by grants from the City of Seattle and King County Department of Natural Resources, with additional support from WDFW’s Warmwater Fish Enhancement Program. “The training of fisheries personnel in the future will increasingly include underwater techniques and their application to fisheries methods. Technological advances in the design and manufacture of diving gear and visual monitoring devices have reduced the costs and increased the safety and accessibility of this equipment. A modern fisheries organization can now afford underwater methods and should incorporate them into its program.” Gene S. Helfman (1983) BSTRACT Direct underwater observations were used to characterize habitat use and to quantify abundance o

Prevalence, Biomechanics, and Pathologies of the Meniscofemoral Ligaments: A Systematic Review

To systematically review the literature to examine current understanding of the meniscofemoral ligaments (MFLs), their function, their importance in clinical management, and known anatomical variants. A systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using PubMed, EMBASE, and Cochrane databases. Studies were included if they reported on the biomechanical, radiographic, or arthroscopic evaluation of human MFLs, or if they reported on an anatomical variant. These were then categorized as cadaveric, radiographic, or clinical. Biomechanical, radiographic, patient-reported, and functional outcomes data were recorded. Forty-seven studies were included in the qualitative analysis, and 26 of them were included in the quantitative analysis. Of these, there were 15 cadaveric, 3 arthroscopic, and 9 radiographic studies that reported on the prevalence of MFLs. Overall, when looking at all modalities, the presence of either the anterior or posterior MFL (aMFL, pMFL) has been noted to be 70.8%, with it being the aMFL 17.4% and the pMFL 40.6%. The presence of both ligaments occurs in approximately 17.6% of individuals. Eleven reported on mean MFL length and thickness. When evaluating mean length in both men and women, the aMFL has been reported between 21.6 and 28.3 mm and the pMFL length in this population is between 23.4 and 31.2 mm. Five reported on cross-sectional area. Nine additional papers report anatomical variants. This review shows that there continues to be a variable incidence of MFLs reported in the literature, but our understanding of their function continues to broaden. A growing number of anatomic and biomechanical studies have demonstrated the importance of the MFLs in supporting knee stability. Specifically, the MFLs serve an important role in protecting the lateral meniscus and augmenting the function of the posterior cruciate ligament. Our findings will aid the clinician in both identifying and treating pathologies of the meniscofemoral ligaments