Contrasting alterations to synaptic and intrinsic properties in upper-cervical superficial dorsal horn neurons following acute neck muscle inflammation

Background: Acute and chronic pain in axial structures, like the back and neck, are difficult to treat, and have incidence as high as 15%. Surprisingly, most preclinical work on pain mechanisms focuses on cutaneous structures in the limbs and animal models of axial pain are not widely available. Accordingly, we developed a mouse model of acute cervical muscle inflammation and assessed the functional properties of superficial dorsal horn (SDH) neurons.<p></p> Results: Male C57/Bl6 mice (P24-P40) were deeply anaesthetised (urethane 2.2?g/kg i.p) and the rectus capitis major muscle (RCM) injected with 40??l of 2% carrageenan. Sham animals received vehicle injection and controls remained anaesthetised for 2?hrs. Mice in each group were sacrificed at 2?hrs for analysis. c-Fos staining was used to determine the location of activated neurons. c-Fos labelling in carrageenan-injected mice was concentrated within ipsilateral (87% and 63% of labelled neurons in C1 and C2 segments, respectively) and contralateral laminae I - II with some expression in lateral lamina V. c-Fos expression remained below detectable levels in control and sham animals. In additional experiments, whole cell recordings were obtained from visualised SDH neurons in transverse slices in the ipsilateral C1 and C2 spinal segments. Resting membrane potential and input resistance were not altered. Mean spontaneous EPSC amplitude was reduced by ~20% in neurons from carrageenan-injected mice versus control and sham animals (20.63???1.05 vs. 24.64???0.91 and 25.87???1.32 pA, respectively). The amplitude (238???33 vs. 494???96 and 593???167 pA) and inactivation time constant (12.9???1.5 vs. 22.1???3.6 and 15.3???1.4?ms) of the rapid A type potassium current (IAr), the dominant subthreshold current in SDH neurons, were reduced in carrageenan-injected mice.<p></p> Conclusions: Excitatory synaptic drive onto, and important intrinsic properties (i.e., IAr) within SDH neurons are reduced two hours after acute muscle inflammation. We propose this time point represents an important transition period between peripheral and central sensitisation with reduced excitatory drive providing an initial neuroprotective mechanism during the early stages of the progression towards central sensitisation

A response to the House of Commons Education Committee report on Multi-Academy Trusts

The number of schools joining multi-academy trusts has grown over the last five years, and it is expected that this growth will continue. The House of Commons Education Committee has, as a result, looked into the performance and role of these trusts. Steven J Courtney, Ruth McGinity, Steven Jones, Robert Hindle, Stephen M Rayner and Belinda Hughes focus on four key aspects of the Committee’s report and argue that broader questions about the government’s policy remain untouched

Infrared Properties of High Redshift and X-ray Selected AGN Samples

The NASA/ISO Key Project on active galactic nuclei (AGN) seeks to better understand the broad-band spectral energy distributions (SEDs) of these sources from radio to X-rays, with particular emphasis on infrared properties. The ISO sample includes a wide variety of AGN types and spans a large redshift range. Two subsamples are considered herein: 8 high-redshift (1 < z < 4.7) quasars; and 22 hard X-ray selected sources. The X-ray selected AGN show a wide range of IR continuum shapes, extending to cooler colors than the optical/radio sample of Elvis et al. (1994). Where a far-IR turnover is clearly observed, the slopes are < 2.5 in all but one case so that non-thermal emission remains a possibility. The highest redshift quasars show extremely strong, hot IR continua requiring ~ 100 solar masses of 500 - 1000 Kelvin dust with ~ 100 times weaker optical emission. Possible explanations for these unusual properties include: reflection of the optical light from material above/below a torus; strong obscuration of the optical continuum; or an intrinsic deficit of optical emission.Comment: 8 pages, 3 figures (2 color), to be published in the Springer Lecture Notes of Physics Series as part of the proceedings for "ISO Surveys of a Dusty Universe," a workshop held at Ringberg Castle, Germany, November 8 - 12, 1999. Requires latex style files for this series: cl2emult.cls, cropmark.sty, lnp.sty, sprmindx.sty, subeqnar.sty (included with submission

The Far-Infrared Spectral Energy Distributions of X-ray-selected Active Galaxies

[Abridged] We present ISO far-infrared (IR) observations of 21 hard X-ray selected AGN from the HEAO-1 A2 sample. We compare the far-IR to X-ray spectral energy distributions (SEDs) of this sample with various radio and optically selected AGN samples. The hard-X-ray selected sample shows a wider range of optical/UV shapes extending to redder near-IR colors. The bluer objects are Seyfert 1s, while the redder AGN are mostly intermediate or type 2 Seyferts. This is consistent with a modified unification model in which the amount of obscuring material increases with viewing angle and may be clumpy. Such a scenario, already suggested by differing optical/near-IR spectroscopic and X-ray AGN classifications, allows for different amounts of obscuration of the continuum emission in different wavebands and of the broad emission line region which results in a mixture of behaviors for AGN with similar optical emission line classifications. The resulting limits on the column density of obscuring material through which we are viewing the redder AGN are 100 times lower than for the standard optically thick torus models. The resulting decrease in optical depth of the obscuring material allows the AGN to heat more dust at larger radial distances. We show that an AGN-heated, flared, dusty disk with mass 10^9 solar and size of few hundred pc is able to generate optical-far-IR SEDs which reproduce the wide range of SEDs present in our sample with no need for an additional starburst component to generate the long-wavelength, cooler part of the IR continuum.Comment: 40 pages, 14 figures, accepted for publication in Astrophysical Journal, V. 590, June 10, 200

An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis.

Thousands of epigenomic data sets have been generated in the past decade, but it is difficult for researchers to effectively use all the data relevant to their projects. Systematic integrative analysis can help meet this need, and the VISION project was established for validated systematic integration of epigenomic data in hematopoiesis. Here, we systematically integrated extensive data recording epigenetic features and transcriptomes from many sources, including individual laboratories and consortia, to produce a comprehensive view of the regulatory landscape of differentiating hematopoietic cell types in mouse. By using IDEAS as our integrative and discriminative epigenome annotation system, we identified and assigned epigenetic states simultaneously along chromosomes and across cell types, precisely and comprehensively. Combining nuclease accessibility and epigenetic states produced a set of more than 200,000 candidate cis-regulatory elements (cCREs) that efficiently capture enhancers and promoters. The transitions in epigenetic states of these cCREs across cell types provided insights into mechanisms of regulation, including decreases in numbers of active cCREs during differentiation of most lineages, transitions from poised to active or inactive states, and shifts in nuclease accessibility of CTCF-bound elements. Regression modeling of epigenetic states at cCREs and gene expression produced a versatile resource to improve selection of cCREs potentially regulating target genes. These resources are available from our VISION website to aid research in genomics and hematopoiesis.National Institute of Diabetes and Digestive and Kidney Diseases (grant number R24DK106766-01A1), the National Human Genome Research Institute (grant number U54HG006998

A threatened ecological community: Research advances and priorities for Banksia woodlands

The rapid expansion of urban areas worldwide is leading to native habitat loss and ecosystem fragmentation and degradation. Although the study of urbanisation\u27s impact on biodiversity is gaining increasing interest globally, there is still a disconnect between research recommendations and urbanisation strategies. Expansion of the Perth metropolitan area on the Swan Coastal Plain in south-western Australia, one of the world\u27s thirty-six biodiversity hotspots, continues to affect the Banksia Woodlands (BWs) ecosystem, a federally listed Threatened Ecological Community (TEC). Here, we utilise the framework of a 1989 review of the state of knowledge of BWs ecology and conservation to examine scientific advances made in understanding the composition, processes and functions of BWs and BWs\u27 species over the last 30 years. We highlight key advances in our understanding of the ecological function and role of mechanisms in BWs that are critical to the management of this ecosystem. The most encouraging change since 1989 is the integration of research between historically disparate ecological disciplines. We outline remaining ecological knowledge gaps and identify key research priorities to improve conservation efforts for this TEC. We promote a holistic consideration of BWs with our review providing a comprehensive document that researchers, planners and managers may reference. To effectively conserve ecosystems threatened by urban expansion, a range of stakeholders must be involved in the development and implementation of best practices to conserve and maintain both biodiversity and human wellbeing

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Intravenous immunoglobulin and rituximab versus placebo treatment of antibody-associated psychosis: study protocol of a randomised phase IIa double-blinded placebo-controlled trial (SINAPPS2)

Abstract: Background: Evidence is conflicting about a causal role of inflammation in psychosis and, specifically, regarding antibodies binding to neuronal membrane targets, especially N-methyl-D-aspartate receptors. NMDAR, LGI1 and GABA-A antibodies were found more prevalent in people with psychosis than in healthy controls. We aim to test whether these antibodies are pathogenic and may cause isolated psychosis. The SINAPPS2 phase IIa double-blinded randomised controlled trial will test the efficacy and safety of immunoglobulin and rituximab treatment versus placebo for patients with acute psychosis symptoms as added to psychiatric standard of care. Methods: We will screen approximately 2500 adult patients with acute psychosis to identify 160 with antibody-positive psychosis without co-existing neurological disease and recruit about 80 eligible participants to the trial in the period from September 2017 to September 2021 across the UK. Eligible patients will be randomised 1:1 either to intravenous immunoglobulin (IVIG) followed by rituximab or to placebo infusions of 1% albumin followed by 0.9% sodium chloride, respectively. To detect a time-to-symptomatic-recovery hazard ratio of 0.322 with a power of 80%, 56 participants are needed to complete the trial, allowing for up to 12 participants to drop out of each group. Eligible patients will be randomised and assessed at baseline within 4 weeks of their eligibility confirmation. The treatment will start with IVIG or 1% albumin placebo infusions over 2–4 consecutive days no later than 7 days from baseline. It will continue 4–5 weeks later with a rituximab or sodium chloride placebo infusion and will end 2–3 weeks after this with another rituximab or placebo infusion. The primary outcome is the time to symptomatic recovery defined as symptomatic remission sustained for at least 6 months on the following Positive and Negative Syndrome Scale items: P1, P2, P3, N1, N4, N6, G5 and G9. Participants will be followed for 12 months from the first day of treatment or, where sustained remission begins after the first 6 months, for an additional minimum of 6 months to assess later response. Discussion: The SINAPPS2 trial aims to test whether immunotherapy is efficacious and safe in psychosis associated with anti-neuronal membrane antibodies. Trial registration: ISRCTN, 11177045. Registered on 2 May 2017. EudraCT, 2016-000118-31. Registered on 22 November 2016. ClinicalTrials.gov, NCT03194815. Registered on 21 June 2017

NEDDylation is essential for Kaposi's sarcoma-associated herpesvirus latency and lytic reactivation and represents a novel anti-KSHV target.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), which are aggressive malignancies associated with immunocompromised patients. For many non-viral malignancies, therapeutically targeting the ubiquitin proteasome system (UPS) has been successful. Likewise, laboratory studies have demonstrated that inhibition of the UPS might provide a promising avenue for the treatment of KSHV-associated diseases. The largest class of E3 ubiquitin ligases are the cullin-RING ligases (CRLs) that are activated by an additional ubiquitin-like protein, NEDD8. We show that pharmacological inhibition of NEDDylation (using the small molecule inhibitor MLN4924) is cytotoxic to PEL cells by inhibiting NF-κB. We also show that CRL4B is a novel regulator of latency as its inhibition reactivated lytic gene expression. Furthermore, we uncovered a requirement for NEDDylation during the reactivation of the KSHV lytic cycle. Intriguingly, inhibition prevented viral DNA replication but not lytic cycle-associated gene expression, highlighting a novel mechanism that uncouples these two features of KSHV biology. Mechanistically, we show that MLN4924 treatment precluded the recruitment of the viral pre-replication complex to the origin of lytic DNA replication (OriLyt). These new findings have revealed novel mechanisms that regulate KSHV latency and reactivation. Moreover, they demonstrate that inhibition of NEDDylation represents a novel approach for the treatment of KSHV-associated malignancies