Is There a Role for Treating Inflammation in Moyamoya Disease?: A Review of Histopathology, Genetics, and Signaling Cascades

Moyamoya disease is a slowly progressing steno-occlusive condition affecting the cerebrovasculature. Affecting the terminal internal carotid arteries (ICA) and there branches, bilaterally, a resulting in a fine vascular network in the base of the brain to allow for compensation of the stenosed vessels. While there is obvious evidence of the involvement of inflammatory proteins in the condition, this has historically not been acknowledged as a causal factor. Here we describe the fundamental histopathology, genetics, and signaling cascades involved in moyamoya and debate whether these factors can be linked as causal factor for the condition or whether they are simply a secondary result of the ischemia described in the condition. A particular focus has been placed on the multitude of signaling cascades linked to the condition as these are viewed as having the greatest therapeutic potential. As such we hope to draw some novel insight into potential diagnostic and therapeutic inflammatory targets in the condition

Self-duality of the D1-D5 near-horizon

We explore fermionic T-duality and self-duality in the geometry AdS3 x S3 x T4 in type IIB supergravity. We explicitly construct the Killing spinors and the fermionic T-duality isometries and show that the geometry is self-dual under a combination of two bosonic AdS3 T-dualities, four fermionic T-dualities and either two additional T-dualities along T4 or two T-dualities along S3. In addition, we show that the presence of a B-field acts as an obstacle to self-duality, a property attributable to S- duality and fermionic T-duality not commuting. Finally, we argue that fermionic T-duality may be extended to CY2 = K3, a setting where we cannot explicitly construct the Killing spinors.Comment: 24 pages, references added, changes made to reinforce the point that S-duality and fermionic T-duality generically do not commute, version accepted to JHE

Ozone-derived Oxysterols Affect Liver X Receptor (LXR) Signaling: A POTENTIAL ROLE FOR LIPID-PROTEIN ADDUCTS

When inhaled, ozone (O3) interacts with cholesterols of airway epithelial cell membranes or the lung-lining fluid, generating chemically reactive oxysterols. The mechanism by which O3-derived oxysterols affect molecular function is unknown. Our data show that in vitro exposure of human bronchial epithelial cells to O3 results in the formation of oxysterols, epoxycholesterol-α and -β and secosterol A and B (Seco A and Seco B), in cell lysates and apical washes. Similarly, bronchoalveolar lavage fluid obtained from human volunteers exposed to O3 contained elevated levels of these oxysterol species. As expected, O3-derived oxysterols have a pro-inflammatory effect and increase NF-κB activity. Interestingly, expression of the cholesterol efflux pump ATP-binding cassette transporter 1 (ABCA1), which is regulated by activation of the liver X receptor (LXR), was suppressed in epithelial cells exposed to O3. Additionally, exposure of LXR knock-out mice to O3 enhanced pro-inflammatory cytokine production in the lung, suggesting LXR inhibits O3-induced inflammation. Using alkynyl surrogates of O3-derived oxysterols, our data demonstrate adduction of LXR with Seco A. Similarly, supplementation of epithelial cells with alkynyl-tagged cholesterol followed by O3 exposure causes observable lipid-LXR adduct formation. Experiments using Seco A and the LXR agonist T0901317 (T09) showed reduced expression of ABCA1 as compared with stimulation with T0901317 alone, indicating that Seco A-LXR protein adduct formation inhibits LXR activation by traditional agonists. Overall, these data demonstrate that O3-derived oxysterols have pro-inflammatory functions and form lipid-protein adducts with LXR, thus leading to suppressed cholesterol regulatory gene expression and providing a biochemical mechanism mediating O3-derived formation of oxidized lipids in the airways and subsequent adverse health effects

Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder

Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the discovery that the intensity of threat-avoidance behaviour is altered by the benzodiazepine anxiolytic lorazepam. However, these studies used healthy human participants, raising questions as to their validity in anxiety disorder patients, as well as their generalisability beyond GABAergic benzodiazepine drugs. BNC210 is a novel negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor and we recently used functional Magnetic Resonance Imaging to show it reduced amygdala responses to fearful faces in generalised anxiety disorder patients. Here we report the effect of BNC210 on the intensity of threat-avoidance behaviour in 21 female GAD patients from the same cohort. We used the Joystick Operated Runway Task as our behavioural measure, which is a computerised human translation of the Mouse Defense Test Battery, and the Spielberger state anxiety inventory as our measure of state affect. Using a repeated-measures, within-subjects design we assessed the effect of BNC210 at two dose levels versus placebo (300 mg and 2000 mg) upon two types of threat-avoidance behaviour (Flight Intensity and Risk Assessment Intensity). We also tested the effects of 1.5 mg of the benzodiazepine lorazepam as an active control. BNC210 significantly reduced Flight Intensity relative to placebo and the low dose of BNC210 also significantly reduced self-reported state anxiety. Risk Assessment Intensity was not significantly affected. Results show both human defensive behaviour and state anxiety are influenced by cholinergic neurotransmission and there provide converging evidence that this system has potential as a novel target for anxiolytic pharmacotherapy

Thermodynamics of a fast-moving Greenlandic outlet glacier revealed by fiber-optic distributed temperature sensing

Funding: This research was funded by the European Research Council as part of the RESPONDER project under the European Union’s Horizon 2020 research and innovation program (grant 683043). R.L. and T.R.C. were supported by Natural Environment Research Council Doctoral Training Partnership studentships (grant NE/ L002507/1). B.H. was supported by a HEFCW/Aberystwyth University Capital Equipment Grant.Measurements of ice temperature provide crucial constraints on ice viscosity and the thermodynamic processes occurring within a glacier. However, such measurements are presently limited by a small number of relatively coarse-spatial-resolution borehole records, especially for ice sheets. Here, we advance our understanding of glacier thermodynamics with an exceptionally high-vertical-resolution (~0.65 m), distributed-fiber-optic temperature-sensing profile from a 1043-m borehole drilled to the base of Sermeq Kujalleq (Store Glacier), Greenland. We report substantial but isolated strain heating within interglacial-phase ice at 208 to 242 m depth together with strongly heterogeneous ice deformation in glacial-phase ice below 889 m. We also observe a high-strain interface between glacial- and interglacial-phase ice and a 73-m-thick temperate basal layer, interpreted as locally formed and important for the glacier's fast motion. These findings demonstrate notable spatial heterogeneity, both vertically and at the catchment scale, in the conditions facilitating the fast motion of marine-terminating glaciers in Greenland.Publisher PDFPeer reviewe

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers

Incarceration history and risk of HIV and hepatitis C virus acquisition among people who inject drugs: a systematic review and meta-analysis

Background People who inject drugs (PWID) experience a high prevalence of incarceration and might be at high risk of HIV and hepatitis C virus (HCV) infection during or after incarceration. We aimed to assess whether incarceration history elevates HIV or HCV acquisition risk among PWID. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO databases for studies in any language published from Jan 1, 2000 until June 13, 2017 assessing HIV or HCV incidence among PWID. We included studies that measured HIV or HCV incidence among community-recruited PWID. We included only studies reporting original results and excluded studies that evaluated incident infections by self-report. We contacted authors of cohort studies that met the inclusion or exclusion criteria, but that did not report on the outcomes of interest, to request data. We extracted and pooled data from the included studies using random-effects meta-analyses to quantify the associations between recent (past 3, 6, or 12 months or since last follow-up) or past incarceration and HIV or HCV acquisition (primary infection or reinfection) risk among PWID. We assessed the risk of bias of included studies using the Newcastle-Ottawa Scale. Between-study heterogeneity was evaluated using the I2 statistic and the P-value for heterogeneity. Findings We included published results from 20 studies and unpublished results from 21 studies. These studies originated from Australasia, western and eastern Europe, North and Latin America, and east and southeast Asia. Recent incarceration was associated with an 81% (relative risk [RR] 1·81, 95% CI 1·40–2·34) increase in HIV acquisition risk, with moderate heterogeneity between studies (I2=63·5%; p=0·001), and a 62% (RR 1·62, 95% CI 1·28–2·05) increase in HCV acquisition risk, also with moderate heterogeneity between studies (I2=57·3%; p=0·002). Past incarceration was associated with a 25% increase in HIV (RR 1·25, 95% CI 0·94–1·65) and a 21% increase in HCV (1·21, 1·02–1·43) acquisition risk. Interpretation Incarceration is associated with substantial short-term increases in HIV and HCV acquisition risk among PWID and could be a significant driver of HCV and HIV transmission among PWID. These findings support the need for developing novel interventions to minimise the risk of HCV and HIV acquisition, including addressing structural risks associated with drug laws and excessive incarceration of PWID

Measurement of the branching ratios of the Z0 into heavy quarks

We measure the hadronic branching ratios of the Z0 boson into heavy quarks: Rb=Gamma(Z0->bb)/Gamma(Z0->hadrons) and Rc=Gamma(Z0->cc/Gamma(Z0->hadrons) using a multi-tag technique. The measurement was performed using about 400,000 hadronic Z0 events recorded in the SLD experiment at SLAC between 1996 and 1998. The small and stable SLC beam spot and the CCD-based vertex detector were used to reconstruct bottom and charm hadron decay vertices with high efficiency and purity, which enables us to measure most efficiencies from data. We obtain, Rb=0.21604 +- 0.00098(stat.) +- 0.00073(syst.) -+ 0.00012(Rc) and, Rc= 0.1744 +- 0.0031(stat.) +- 0.0020(syst.) -+ 0.0006(Rb)Comment: 37 pages, 8 figures, to be submitted to Phys. Rev. D version 2: changed title to ratios, used common D production fractions for Rb and Rc and corrected Zgamma interference. Identical to PRD submissio

Direct Measurements of A_b and A_c using Vertex/Kaon Charge Tags at SLD

Exploiting the manipulation of the SLC electron-beam polarization, we present precise direct measurements of the parity violation parameters A_c and A_b in the Z boson - c quark and Z boson - b quark coupling. Quark/antiquark discrimination is accomplished via a unique algorithm that takes advantage of the precise SLD CCD vertex detector, employing the net charge of displaced vertices as well as the charge of kaons that emanate from those vertices. From the 1996-98 sample of 400,000 Z decays, produced with an average beam polarization of 73.4%, we find A_c = 0.673 +/- 0.029 (stat.) +/- 0.023 (syst.) and A_b = 0.919 +/- 0.018 (stat.) +/- 0.017 (syst.).Comment: 11 pages, 2 figures, 2 tables, to be submitted to Physical Review Letters; version 2 reflects changes suggested by the refere