Is heavy eccentric calf training superior to wait-and-see, sham rehabilitation, traditional physiotherapy and other exercise interventions for pain and function in mid-portion Achilles tendinopathy?

Background: Mid-portion Achilles tendinopathy (AT) is prevalent amongst athletic and non-athletic populations with pain, stiffness and impaired function typically reported. While different management options exist, loading protocols remain the best available intervention and have been shown to be effective in the management of AT. Trials investigating loading in AT have used a variety of different protocols, and recent narrative reviews suggest that no protocol is superior to another when comparing outcomes in pain and function. However, there has been no systematic review or meta-analysis completed to determine this. Furthermore, the narrative review did not consider wait-and-see or sham interventions, thus a systematic review and met-analysis which includes wait-and see or sham interventions is warranted. Methods: A systematic review and meta-analyses will be conducted as per the PRISMA guidelines. The databases PUBMED, CINAHL (Ovid) and CINAHL (EBSCO) will be searched for articles published from inception to 31 December 2017. Our search focuses on studies examining the improvement of pain and function when completing a loading program for mid-portion AT. Only randomised/ quasi-randomised trials will be included while case reports and case series will be excluded. The primary outcome assessing pain and function will be the Victorian Institute Sports Assessment - Achilles (VISA-A). Two reviewers will screen articles, extract data and assess the risk of bias independently with a third reviewer resolving any disagreements between the two reviewers. A meta-analysis will then be performed on the data (if appropriate) to determine if the traditional heavy load calf training protocol described by Alfredson is superior to wait-and-see, sham intervention, traditional physiotherapy, and other forms of exercise rehabilitation. Discussion: This systematic review and meta-analysis will allow us to investigate if there are difference in pain and function when comparing wait-and-see, sham interventions, traditional physiotherapy and different exercise interventions to the traditional heavy eccentric calf training protocol for mid-portion Achilles tendon pain. Systematic review registration: PROSPERO registration number CRD42018084493

The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state

We introduce and analyze a minimal model of epigenetic silencing in budding yeast, built upon known biomolecular interactions in the system. Doing so, we identify the epigenetic marks essential for the bistability of epigenetic states. The model explicitly incorporates two key chromatin marks, namely H4K16 acetylation and H3K79 methylation, and explores whether the presence of multiple marks lead to a qualitatively different systems behavior. We find that having both modifications is important for the robustness of epigenetic silencing. Besides the silenced and transcriptionally active fate of chromatin, our model leads to a novel state with bivalent (i.e., both active and silencing) marks under certain perturbations (knock-out mutations, inhibition or enhancement of enzymatic activity). The bivalent state appears under several perturbations and is shown to result in patchy silencing. We also show that the titration effect, owing to a limited supply of silencing proteins, can result in counter-intuitive responses. The design principles of the silencing system is systematically investigated and disparate experimental observations are assessed within a single theoretical framework. Specifically, we discuss the behavior of Sir protein recruitment, spreading and stability of silenced regions in commonly-studied mutants (e.g., sas2, dot1) illuminating the controversial role of Dot1 in the systems biology of yeast silencing.Comment: Supplementary Material, 14 page

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition

Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modelling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4BY358C mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioural assays, PDE4BY358C mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4BY358C mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 hours, was decreased at 7 days in PDE4BY358C mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signalling by PDE4B in a very late phase of consolidation. No effect of the PDE4BY358C mutation was observed in the pre-pulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory

H2A.Z Demarcates Intergenic Regions of the Plasmodium falciparum Epigenome That Are Dynamically Marked by H3K9ac and H3K4me3

Epigenetic regulatory mechanisms and their enzymes are promising targets for malaria therapeutic intervention; however, the epigenetic component of gene expression in P. falciparum is poorly understood. Dynamic or stable association of epigenetic marks with genomic features provides important clues about their function and helps to understand how histone variants/modifications are used for indexing the Plasmodium epigenome. We describe a novel, linear amplification method for next-generation sequencing (NGS) that allows unbiased analysis of the extremely AT-rich Plasmodium genome. We used this method for high resolution, genome-wide analysis of a histone H2A variant, H2A.Z and two histone H3 marks throughout parasite intraerythrocytic development. Unlike in other organisms, H2A.Z is a constant, ubiquitous feature of euchromatic intergenic regions throughout the intraerythrocytic cycle. The almost perfect colocalisation of H2A.Z with H3K9ac and H3K4me3 suggests that these marks are preferentially deposited on H2A.Z-containing nucleosomes. By performing RNA-seq on 8 time-points, we show that acetylation of H3K9 at promoter regions correlates very well with the transcriptional status whereas H3K4me3 appears to have stage-specific regulation, being low at early stages, peaking at trophozoite stage, but does not closely follow changes in gene expression. Our improved NGS library preparation procedure provides a foundation to exploit the malaria epigenome in detail. Furthermore, our findings place H2A.Z at the cradle of P. falciparum epigenetic regulation by stably defining intergenic regions and providing a platform for dynamic assembly of epigenetic and other transcription related complexes

‘Even though it might take me a while, in the end, I understand it’: a longitudinal case study of interactions between a conceptual change strategy and student motivation, interest and confidence

Although there have been many investigations of the social, motivational, and emotional aspects of conceptual change, there have been few studies investigating the intersection of these factors with cognitive aspects in the regular classroom. Using a conceptual change approach, this case study reports experiences of a student of low to average prior attainment who achieved high levels of conceptual gains in five science topics over a two-year period. Her experience in the cognitive, social and affective domains was probed through analysis of interviews, student artefacts, video recordings of classroom learning, pre/post-tests and questionnaire results. For this student, peripheral or incidental persuasion of belonging to a supportive small group initially led to greater engagement with the construction of understanding through production of multiple student-generated representations, resulting in improved self-confidence and high levels of conceptual change. Evidence of transfer from performance to mastery approach goals, adoption of positive activating emotions and increased interest in science were observed. This study highlights that adoption of a multidimensional conceptual change approach with judicious organisation of small groups to support construction of verbal, pictorial and written representations of understanding may bring about changes in motivational stance, self-confidence and emotions to maximise conceptual change