Histone modifying enzymes play critical roles in many key cellular processes and are appealing proteins for targeting by small molecules in disease. However, while the functions of histone modifying ...enzymes are often linked to epigenetic regulation of the genome, an emerging theme is that these enzymes often also act by non-catalytic and/or non-epigenetic mechanisms. SETD2 (Set2 in yeast) is best known for associating with the transcription machinery and methylating histone H3 on lysine 36 (H3K36) during transcription. This well-characterized molecular function of SETD2 plays a role in fine-tuning transcription, maintaining chromatin integrity, and mRNA processing. Here we give an overview of the various molecular functions and mechanisms of regulation of H3K36 methylation by Set2/SETD2. These fundamental insights are important to understand SETD2’s role in disease, most notably in cancer in which SETD2 is frequently inactivated. SETD2 also methylates non-histone substrates such as α-tubulin which may promote genome stability and contribute to the tumor-suppressor function of SETD2. Thus, to understand its role in disease, it is important to understand and dissect the multiple roles of SETD2 within the cell. In this review we discuss how histone methylation by Set2/SETD2 has led the way in connecting histone modifications in active regions of the genome to chromatin functions and how SETD2 is leading the way to showing that we also have to look beyond histones to truly understand the physiological role of an ‘epigenetic’ writer enzyme in normal cells and in disease.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
2.
New perspectives in epilepsy neuropathology Thom, M.
Neuropathology & applied neurobiology/Neuropathology and applied neurobiology,
February 2018, 2018-02-00, 20180201, Volume:
44, Issue:
1
Journal Article
Peer reviewed
Open access
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Many interesting but practically intractable problems can be reduced to that of finding the ground state of a system of interacting spins; however, finding such a ground state remains computationally ...difficult. It is believed that the ground state of some naturally occurring spin systems can be effectively attained through a process called quantum annealing. If it could be harnessed, quantum annealing might improve on known methods for solving certain types of problem. However, physical investigation of quantum annealing has been largely confined to microscopic spins in condensed-matter systems. Here we use quantum annealing to find the ground state of an artificial Ising spin system comprising an array of eight superconducting flux quantum bits with programmable spin-spin couplings. We observe a clear signature of quantum annealing, distinguishable from classical thermal annealing through the temperature dependence of the time at which the system dynamics freezes. Our implementation can be configured in situ to realize a wide variety of different spin networks, each of which can be monitored as it moves towards a low-energy configuration. This programmable artificial spin network bridges the gap between the theoretical study of ideal isolated spin networks and the experimental investigation of bulk magnetic samples. Moreover, with an increased number of spins, such a system may provide a practical physical means to implement a quantum algorithm, possibly allowing more-effective approaches to solving certain classes of hard combinatorial optimization problems.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
The Mini Mental State Examination (MMSE) is a cognitive test that is commonly used as part of the evaluation for possible dementia.
Objectives
To determine the diagnostic accuracy of the ...Mini‐Mental State Examination (MMSE) at various cut points for dementia in people aged 65 years and over in community and primary care settings who had not undergone prior testing for dementia.
Search methods
We searched the specialised register of the Cochrane Dementia and Cognitive Improvement Group, MEDLINE (OvidSP), EMBASE (OvidSP), PsycINFO (OvidSP), LILACS (BIREME), ALOIS, BIOSIS previews (Thomson Reuters Web of Science), and Web of Science Core Collection, including the Science Citation Index and the Conference Proceedings Citation Index (Thomson Reuters Web of Science). We also searched specialised sources of diagnostic test accuracy studies and reviews: MEDION (Universities of Maastricht and Leuven, www.mediondatabase.nl), DARE (Database of s of Reviews of Effects, via the Cochrane Library), HTA Database (Health Technology Assessment Database, via the Cochrane Library), and ARIF (University of Birmingham, UK, www.arif.bham.ac.uk). We attempted to locate possibly relevant but unpublished data by contacting researchers in this field. We first performed the searches in November 2012 and then fully updated them in May 2014. We did not apply any language or date restrictions to the electronic searches, and we did not use any methodological filters as a method to restrict the search overall.
Selection criteria
We included studies that compared the 11‐item (maximum score 30) MMSE test (at any cut point) in people who had not undergone prior testing versus a commonly accepted clinical reference standard for all‐cause dementia and subtypes (Alzheimer disease dementia, Lewy body dementia, vascular dementia, frontotemporal dementia). Clinical diagnosis included all‐cause (unspecified) dementia, as defined by any version of the Diagnostic and Statistical Manual of Mental Disorders (DSM); International Classification of Diseases (ICD) and the Clinical Dementia Rating.
Data collection and analysis
At least three authors screened all citations.Two authors handled data extraction and quality assessment. We performed meta‐analysis using the hierarchical summary receiver‐operator curves (HSROC) method and the bivariate method.
Main results
We retrieved 24,310 citations after removal of duplicates. We reviewed the full text of 317 full‐text articles and finally included 70 records, referring to 48 studies, in our synthesis. We were able to perform meta‐analysis on 28 studies in the community setting (44 articles) and on 6 studies in primary care (8 articles), but we could not extract usable 2 x 2 data for the remaining 14 community studies, which we did not include in the meta‐analysis. All of the studies in the community were in asymptomatic people, whereas two of the six studies in primary care were conducted in people who had symptoms of possible dementia. We judged two studies to be at high risk of bias in the patient selection domain, three studies to be at high risk of bias in the index test domain and nine studies to be at high risk of bias regarding flow and timing. We assessed most studies as being applicable to the review question though we had concerns about selection of participants in six studies and target condition in one study.
The accuracy of the MMSE for diagnosing dementia was reported at 18 cut points in the community (MMSE score 10, 14‐30 inclusive) and 10 cut points in primary care (MMSE score 17‐26 inclusive). The total number of participants in studies included in the meta‐analyses ranged from 37 to 2727, median 314 (interquartile range (IQR) 160 to 647). In the community, the pooled accuracy at a cut point of 24 (15 studies) was sensitivity 0.85 (95% confidence interval (CI) 0.74 to 0.92), specificity 0.90 (95% CI 0.82 to 0.95); at a cut point of 25 (10 studies), sensitivity 0.87 (95% CI 0.78 to 0.93), specificity 0.82 (95% CI 0.65 to 0.92); and in seven studies that adjusted accuracy estimates for level of education, sensitivity 0.97 (95% CI 0.83 to 1.00), specificity 0.70 (95% CI 0.50 to 0.85). There was insufficient data to evaluate the accuracy of the MMSE for diagnosing dementia subtypes.We could not estimate summary diagnostic accuracy in primary care due to insufficient data.
Authors' conclusions
The MMSE contributes to a diagnosis of dementia in low prevalence settings, but should not be used in isolation to confirm or exclude disease. We recommend that future work evaluates the diagnostic accuracy of tests in the context of the diagnostic pathway experienced by the patient and that investigators report how undergoing the MMSE changes patient‐relevant outcomes.
Entanglement lies at the core of quantum algorithms designed to solve problems that are intractable by classical approaches. One such algorithm, quantum annealing (QA), provides a promising path to a ...practical quantum processor. We have built a series of architecturally scalable QA processors consisting of networks of manufactured interacting spins (qubits). Here, we use qubit tunneling spectroscopy to measure the energy eigenspectrum of two- and eight-qubit systems within one such processor, demonstrating quantum coherence in these systems. We present experimental evidence that, during a critical portion of QA, the qubits become entangled and entanglement persists even as these systems reach equilibrium with a thermal environment. Our results provide an encouraging sign that QA is a viable technology for large-scale quantum computing.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM, UPUK
Efforts to develop useful quantum computers have been blocked primarily by environmental noise. Quantum annealing is a scheme of quantum computation that is predicted to be more robust against noise, ...because despite the thermal environment mixing the system's state in the energy basis, the system partially retains coherence in the computational basis, and hence is able to establish well-defined eigenstates. Here we examine the environment's effect on quantum annealing using 16 qubits of a superconducting quantum processor. For a problem instance with an isolated small-gap anticrossing between the lowest two energy levels, we experimentally demonstrate that, even with annealing times eight orders of magnitude longer than the predicted single-qubit decoherence time, the probabilities of performing a successful computation are similar to those expected for a fully coherent system. Moreover, for the problem studied, we show that quantum annealing can take advantage of a thermal environment to achieve a speedup factor of up to 1,000 over a closed system.
Highlights • Some activity monitors have varying accuracy dependent upon speed/placement site. • Accuracy improves as speed increases and if placed on torso/hips over the limbs. • The Fitbit One ...placed around the waist was the most consistently accurate monitor.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Cognitive decline is increasingly described as a co‐morbidity of temporal lobe epilepsy (TLE). Mechanisms underlying cognitive impairment are not fully understood despite examining clinical factors, ...such as seizure frequency, and cellular mechanisms of excitotoxicity. We review the neuropsychometry evidence for progressive cognitive decline and examine the pathology and neuroimaging evidence supporting a neurodegenerative process in hippocampal sclerosis (HS)‐related TLE. Accelerated cognitive decline is described in groups of adult HS‐related TLE patients. Large childhood studies show early onset of seizures result in poor development of verbal memory and a hindrance in achieving cognitive potential. We discuss HS classification according to different patterns of neuronal loss and correlation to post‐temporal lobectomy cognitive outcomes in refractory TLE patients. Factors such as lateralization of HS pathology, neuronal density and subtype have correlated to cognitive outcomes with varying significance between different studies. Furthermore, alterations in neuronal maturity, regenerative capacity and aberrant connectivity appear to affect cognitive performance post‐operatively suggesting a complex multifactorial process. More recent studies have identified tau pathology being present in HS‐related TLE and correlated to post‐operative cognitive decline in some patients. A traumatic head injury‐related or novel tauopathy has been hypothesized as an underlying process. We discuss the value of prospective and cross‐sectional imaging in assessing cognition and review volumetric magnetic resonance studies with progressive ipsilateral hippocampal atrophy identified to correlate with seizure frequency. Finally, we consider the use of positron emission tomography biomarkers, such as tau tracers, and connectivity studies that may examine in vivo pathways and further explore cognitive decline in TLE.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Aim: To investigate mechanical work, efficiency, and antagonist muscle co‐activation with a view to better understand the cause of the elevated metabolic cost of walking (CW) in older adults.
...Methods: Metabolic, mechanical and electromyographic measurements were made as healthy young (YOU; n = 12, age = 27 ± 3 years) and older (OLD; n = 20, age = 74 ± 3 years) men of equivalent body mass and leg length walked on a treadmill at four speeds (ranging from 0.83 to 1.67 m s−1).
Results: Net (above resting) CW, determined by indirect calorimetry was 31% higher (average across speeds) in OLD (P < 0.05). The integrity of the passive pendulum like interchange of mechanical energies of the centre of mass (COMB), an energy‐saving mechanism, was maintained in OLD. Furthermore, total mechanical work, determined from fluctuations in mechanical energy of COMB and of body segments relative to COMB, was not significantly elevated in OLD. This resulted in a lower efficiency in OLD (−17%, P < 0.05). Co‐activation, temporally quantified from electromyography recordings, was 31% higher in OLD for antagonist muscles of the thigh (P < 0.05). Thigh co‐activation was moderately correlated with CW at three speeds (r = 0.38–0.52, P < 0.05).
Conclusion: Healthy septuagenarians with no gait impairment have an elevated CW which is not explained by an elevation in whole body mechanical work. Increased antagonist muscle co‐activation (possibly an adaptation to ensure adequate joint stability) may offer partial explanation of the elevated CW.
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BFBNIB, DOBA, FSPLJ, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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