Wernicke’s aphasia reflects a combination of acoustic-phonological and semantic control deficits: A case-series comparison of Wernicke’s aphasia, semantic dementia and semantic aphasia

Wernicke’s aphasia (WA) is the classical neurological model of comprehension impairment and, as a result, the posterior temporal lobe is assumed to be critical to semantic cognition. This conclusion is potentially confused by (a) the existence of patient groups with semantic impairment following damage to other brain regions (semantic dementia and semantic aphasia) and (b) an ongoing debate about the underlying causes of comprehension impairment in WA. By directly comparing these three patient groups for the first time, we demonstrate that the comprehension impairment in Wernicke’s aphasia is best accounted for by dual deficits in acoustic-phonological analysis (associated with pSTG) and semantic cognition (associated with pMTG and angular gyrus). The WA group were impaired on both nonverbal and verbal comprehension assessments consistent with a generalised semantic impairment. This semantic deficit was most similar in nature to that of the semantic aphasia group suggestive of a disruption to semantic control processes. In addition, only the WA group showed a strong effect of input modality on comprehension, with accuracy decreasing considerably as acoustic-phonological requirements increased. These results deviate from traditional accounts which emphasise a single impairment and, instead, implicate two deficits underlying the comprehension disorder in WA.

Recombinant anti-EspA antibodies block Escherichia coli O157:H7-induced attaching and effacing lesions in vitro

Intimin and EspA proteins are virulence factors expressed by attaching and effacing Escherichia coli (AEEC) such as enteropathogenic and enterohaemorrhagic E. coli. The EspA protein makes up a filament structure forming part of the type III secretion system (TTSS) that delivers effector proteins to the host epithelial cell. Bacterial surface displayed intimin interacts with translocated intimin receptor in the host cell membrane leading to intimate attachment of the bacterium and subsequent attaching and effacing lesions. Here, we have assessed the use of recombinant monoclonal antibodies against E. coli O157:147 EspA and intimin for the disruption of AEEC interaction with the host cell. Anti-gamma intimin antibodies did not reduce either adhesion of E. coli O157:H7 to host cell mono-layers or subsequent host cell actin rearrangement. Anti-EspA antibodies similarly had no effect on bacterial adhesion however they had a marked effect upon E. coli O157:H7-induced host cell actin rearrangement, where both monoclonal and polyclonal antibodies completely blocked cytoskeletal changes within the host cell. Furthermore, these anti-EspA antibodies were shown to reduce actin rearrangement induced by some but not all other AEEC serotypes tested. Both polyclonal and monoclonal antibodies could be used to label E. coli O157 EspA filaments and these immunoreagents did not inhibit the formation of such filaments. This is the first report of monoclonal antibodies to EspA capable of disrupting the TTSS function of E. coli O157:H7. (c) 2005 Elsevier SAS. All rights reserved.

Endosomes: a legitimate platform for the signaling train

Although long regarded as a conduit for the degradation or recycling of cell surface receptors, the endosomal system is also an essential site of signal transduction. Activated receptors accumulate in endosomes, and certain signaling components are exclusively localized to endosomes. Receptors can continue to transmit signals from endosomes that are different from those that arise from the plasma membrane, resulting in distinct physiological responses. Endosomal signaling is widespread in metazoans and plants, where it transmits signals for diverse receptor families that regulate essential processes including growth, differentiation and survival. Receptor signaling at endosomal membranes is tightly regulated by mechanisms that control agonist availability, receptor coupling to signaling machinery, and the subcellular localization of signaling components. Drugs that target mechanisms that initiate and terminate receptor signaling at the plasma membrane are widespread and effective treatments for disease. Selective disruption of receptor signaling in endosomes, which can be accomplished by targeting endosomal-specific signaling pathways or by selective delivery of drugs to the endosomal network, may provide novel therapies for disease.

Recycling and resensitization of the neurokinin 1 receptor: influence of agonist concentration and Rab GTPases

Substance P (SP) induces endocytosis and recycling of the neurokinin 1 receptor (NK1R) in endothelial cells and spinal neurons at sites of inflammation and pain, and it is thus important to understand the mechanism and function of receptor trafficking. We investigated how the SP concentration affects NK1R trafficking and determined the role of Rab GTPases in trafficking. NK1R trafficking was markedly influenced by the SP concentration. High SP (10 nM) induced translocation of the NK1R and beta-arrestin 1 to perinuclear sorting endosomes containing Rab5a, where NK1R remained for >60 min. Low SP (1 nM) induced translocation of the NK1R to early endosomes located immediately beneath the plasma membrane that also contained Rab5a and beta-arrestin 1, followed by rapid recycling of the NK1R. Overexpression of Rab5a promoted NK1R translocation to perinuclear sorting endosomes, whereas the GTP binding-deficient mutant Rab5aS34N caused retention of the NK1R in superficial early endosomes. NK1R translocated from superficial early endosomes to recycling endosomes containing Rab4a and Rab11a, and Rab11aS25N inhibited NK1R recycling. Rapid NK1R recycling coincided with resensitization of SP-induced Ca2+ mobilization and with the return of surface SP binding sites. Resensitization was minimally affected by inhibition of vacuolar H(+)-ATPase and phosphatases but was markedly suppressed by disruption of Rab4a and Rab11a. Thus, whereas beta-arrestins mediate NK1R endocytosis, Rab5a regulates translocation between early and sorting endosomes, and Rab4a and Rab11a regulate trafficking through recycling endosomes. We have thus identified a new function of Rab5a as a control protein for directing concentration-dependent trafficking of the NK1R into different intracellular compartments and obtained evidence that Rab4a and Rab11a contribute to G-protein-coupled receptor recycling from early endosomes.

Hypoxia suppresses glutamate transport in astrocytes

Glutamate uptake by astrocytes is fundamentally important in the regulation of CNS function. Disruption of uptake can lead to excitotoxicity and is implicated in various neurodegenerative processes as well as a consequence of hypoxic/ischemic events. Here, we investigate the effect of hypoxia on activity and expression of the key glutamate transporters excitatory amino acid transporter 1 (EAAT1) [GLAST (glutamate-aspartate transporter)] and EAAT2 [GLT-1 (glutamate transporter 1)]. Electrogenic, Na+-dependent glutamate uptake was monitored via whole-cell patch-clamp recordings from cortical astrocytes. Under hypoxic conditions (2.5 and 1% O2 exposure for 24 h), glutamate uptake was significantly reduced, and pharmacological separation of uptake transporter subtypes suggested that the EAAT2 subtype was preferentially reduced relative to the EAAT1. This suppression was confirmed at the level of EAAT protein expression (via Western blots) and mRNA levels (via real-time PCR). These effects of hypoxia to inhibit glutamate uptake current and EAAT protein levels were not replicated by desferrioxamine, cobalt, FG0041, or FG4496, agents known to mimic effects of hypoxia mediated via the transcriptional regulator, hypoxia-inducible factor (HIF). Furthermore, the effects of hypoxia were not prevented by topotecan, which prevents HIF accumulation. In stark contrast, inhibition of nuclear factor-kappaB (NF-kappaB) with SN50 fully prevented the effects of hypoxia on glutamate uptake and EAAT expression. Our results indicate that prolonged hypoxia can suppress glutamate uptake in astrocytes and that this effect requires activation of NF-kappaB but not of HIF. Suppression of glutamate uptake via this mechanism may be an important contributory factor in hypoxic/ischemic triggered glutamate excitotoxicity.

Salts responsive nanovesicles through π-stacking induced self-assembly of backbone modified tripeptides

A set of backbone modified peptides of general formula Boc-Xx-m-ABA-Yy-OMe where m-ABA is meta-aminobenzoic acid and Xx and Yy are natural amino acids such as Phe, Gly, Pro, Leu, Ile, Tyr and Trp etc., are found to self-assemble into soft nanovesicular structures in methanol-water solution (9:1 by v/v). At higher concentration the peptides generate larger vesicles which are formed through fusion of smaller vesicles. The formation of vesicles has been facilitated through the participation of various noncovalent interactions such as aromatic pi-stacking, hydrogen bonding and hydrophobic interactions. Model study indicates that the pi-stacking induced self-assembly, mediated by m-ABA is essential for well structured vesicles formation. The presence of conformationally rigid m-ABA in the backbone of the peptides also helps to form vesicular structures by restricting the conformational entropy. The vesicular structures get disrupted in presence of various salts such as KCl, CaCl(2), N(n-Bu)(4)Br and (NH(4))(2)SO(4) in methanol-water solution. Fluorescence microscopy and UV studies reveal that the soft nanovesicles encapsulate organic dye molecules such as Rhodamine B and Acridine Orange which could be released through salts induced disruption of vesicles.

The upper end of climate model temperature projections is inconsistent with past warming

Climate models predict a large range of possible future temperatures for a particular scenario of future emissions of greenhouse gases and other anthropogenic forcings of climate. Given that further warming in coming decades could threaten increasing risks of climatic disruption, it is important to determine whether model projections are consistent with temperature changes already observed. This can be achieved by quantifying the extent to which increases in well mixed greenhouse gases and changes in other anthropogenic and natural forcings have already altered temperature patterns around the globe. Here, for the first time, we combine multiple climate models into a single synthesized estimate of future warming rates consistent with past temperature changes. We show that the observed evolution of near-surface temperatures appears to indicate lower ranges (5–95%) for warming (0.35–0.82 K and 0.45–0.93 K by the 2020s (2020–9) relative to 1986–2005 under the RCP4.5 and 8.5 scenarios respectively) than the equivalent ranges projected by the CMIP5 climate models (0.48–1.00 K and 0.51–1.16 K respectively). Our results indicate that for each RCP the upper end of the range of CMIP5 climate model projections is inconsistent with past warming.

Migration, immobility and displacement outcomes following extreme events

There is growing international concern at the rise in the severity of impact and frequency of extreme environmental events, potentially as a manifestation of global environmental change. There is a widely held belief that this trend could be linked with a future rise in the migration or displacement of human populations. However, recent approaches to migration influenced by environmental change call into question the notion that migration can be ascribed in a singular way to particular environmental causes or events. This paper undertakes a systematic review of evidence on population movements associated with weather-related extreme events. The paper demonstrates that in the face of extreme environmental events, it is important to distinguish between three outcomes – migration, displacement, and immobility – each of which interact and respond to multiple drivers. It also proposes a further insight: that both those who move, and those who do not move, may find themselves trapped and vulnerable in the face of such extreme events. A review of evidence suggests that short-term displacement that goes hand-in-hand with loss of life, destruction of property and economic disruption poses significant risks not because it is ‘environmental migration’, but because it represents a failure of adaptation to environmental change.

Direct observations of the evolution of polar cap ionization patches

Patches of ionization are common in the polar ionosphere where their motion and associated density gradients give variable disturbances to High Frequency (HF) radio communications, over-the-horizon radar location errors, and disruption and errors to satellite navigation and communication. Their formation and evolution are poorly understood, particularly under disturbed space weather conditions. We report direct observations of the full evolution of patches during a geomagnetic storm, including formation, polar cap entry, transpolar evolution, polar cap exit, and sunward return flow. Our observations show that modulation of nightside reconnection in the substorm cycle of the magnetosphere helps form the gaps between patches where steady convection would give a “tongue” of ionization (TOI).

Winter and Summer Northern Hemisphere blocking in CMIP5 models

The frequencies of atmospheric blocking in both winter and summer and the changes in them from the 20th to the 21st centuries as simulated in twelve CMIP5 models is analysed. The RCP 8.5 high emission scenario runs are used to represent the 21st century. The analysis is based on the wave-breaking methodology of Pelly and Hoskins (2003a). It differs from the Tibaldi and Molteni (1990) index in viewing equatorward cut-off lows and poleward blocking highs in equal manner as indicating a disruption to the westerlies. 1-dimensional and 2-dimensional diagnostics are applied to identify blocking of the mid-latitude storm-track and also at higher latitudes. Winter blocking frequency is found to be generally underestimated. The models give a decrease in the European blocking maximum in the 21st century, consistent with the results in other studies. There is a mean 21st century winter poleward shift of high- latitude blocking, but little agreement between the models on the details. In summer, Eurasian blocking is also underestimated in the models, whereas it is now too large over the high-latitude ocean basins. A decrease in European blocking frequency in the 21st century model runs is again found. However in summer there is a clear eastward shift of blocking over Eastern Europe and Western Russia, in a region close to the blocking that dominated the Russian summer of 2010. While summer blocking decreases in general, the poleward shift of the storm track into the region of frequent high latitude blocking may mean that the incidence of storms being obstructed by blocks may actually increase.

A mesoscopic modelling approach to anaesthetic action on brain electrical activity

Relating the measurable, large scale, effects of anaesthetic agents to their molecular and cellular targets of action is necessary to better understand the principles by which they affect behavior, as well as enabling the design and evaluation of more effective agents and the better clinical monitoring of existing and future drugs. Volatile and intravenous general anaesthetic agents (GAs) are now known to exert their effects on a variety of protein targets, the most important of which seem to be the neuronal ion channels. It is hence unlikely that anaesthetic effect is the result of a unitary mechanism at the single cell level. However, by altering the behavior of ion channels GAs are believed to change the overall dynamics of distributed networks of neurons. This disruption of regular network activity can be hypothesized to cause the hypnotic and analgesic effects of GAs and may well present more stereotypical characteristics than its underlying microscopic causes. Nevertheless, there have been surprisingly few theories that have attempted to integrate, in a quantitative manner, the empirically well documented alterations in neuronal ion channel behavior with the corresponding macroscopic effects. Here we outline one such approach, and show that a range of well documented effects of anaesthetics on the electroencephalogram (EEG) may be putatively accounted for. In particular we parameterize, on the basis of detailed empirical data, the effects of halogenated volatile ethers (a clinically widely used class of general anaesthetic agent). The resulting model is able to provisionally account for a range of anaesthetically induced EEG phenomena that include EEG slowing, biphasic changes in EEG power, and the dose dependent appearance of anomalous ictal activity, as well as providing a basis for novel approaches to monitoring brain function in both health and disease.

The bile acid receptor TGR5 does not interact with β-arrestins or traffic to endosomes but transmits sustained signals from plasma membrane rafts.

TGR5 is a G protein-coupled receptor that mediates bile acid (BA) effects on energy balance, inflammation, digestion and sensation. The mechanisms and spatiotemporal control of TGR5 signaling are poorly understood. We investigated TGR5 signaling and trafficking in transfected HEK293 cells and colonocytes (NCM460) that endogenously express TGR5. BAs (deoxycholic acid, DCA, taurolithocholic acid, TLCA) and the selective agonists oleanolic acid (OA) and 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide (CCDC) stimulated cAMP formation but did not induce TGR5 endocytosis or recruitment of β-arrestins, assessed by confocal microscopy. DCA, TLCA and OA did not stimulate TGR5 association with β-arrestin 1/2 or G protein-coupled receptor kinase (GRK) 2/5/6, determined by bioluminescence resonance energy transfer. CCDC stimulated a low level of TGR5 interaction with β-arrestin2 and GRK2. DCA induced cAMP formation at the plasma membrane and cytosol, determined using exchange factor directly regulated by cAMP (Epac2)-based reporters, but cAMP signals did not desensitize. AG1478, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, the metalloprotease inhibitor batimastat, and methyl-β-cyclodextrin and filipin, which block lipid raft formation, prevented DCA stimulation of extracellular signal regulated kinase (ERK1/2). BRET analysis revealed TGR5 and EGFR interactions that were blocked by disruption of lipid rafts. DCA stimulated TGR5 redistribution to plasma membrane microdomains, localized by immunogold electron microscopy. Thus, TGR5 does not interact with β-arrestins, desensitize or traffic to endosomes. TGR5 signals from plasma membrane rafts that facilitate EGFR interaction and transactivation. An understanding of the spatiotemporal control of TGR5 signaling provides insights into the actions of BAs and therapeutic TGR5 agonists/antagonists.

Postnatal development of the mucosal immune system and consequences on health in adulthood

The intestinal microbiota is a dynamic multifaceted ecosystem which has evolved a complex and mutually beneficial relationship with the mammalian host. The contribution to host fitness is evident, but in recent years it has become apparent that these commensal microorganisms may exert far more influence over health and disease than previously thought. The gut microbiota are implicated in many aspects of biological function, such as metabolism, angiogenesis and immune development: disruption, especially during the neonatal period, which may impose life-long penalty. Elimination of the microbiota appears difficult, but manipulation of the ratios and dominance of composite populations can be achieved by alterations in diet, rearing environment, antibiotics and/or probiotics. Components of the intestinal microbiota are frequently documented to affect normal function of the mucosal immune system in experimental animals and in domesticated, agricultural species. However, it is not always clear that the effects described are sufficiently well understood to provide a sound basis for commercial intervention. Some microbial interventions may be beneficial to the host under particular circumstances, while detrimental during others. It is essential that we further our understanding of the complex and intricate host-commensal relationship to avoid causing more long-term damage than advantage

An evolutionary innovation perspective on the selection of low and zero carbon technologies in new housing

The Code for Sustainable Homes (the Code) will require new homes in the United Kingdom to be ‘zero carbon’ from 2016. Drawing upon an evolutionary innovation perspective, this paper contributes to a gap in the literature by investigating which low and zero carbon technologies are actually being used by house builders, rather than the prevailing emphasis on the potentiality of these technologies. Using the results from a questionnaire three empirical contributions are made. First, house builders are selecting a narrow range of technologies. Second, these choices are made to minimise the disruption to their standard design and production templates (SDPTs). Finally, the coalescence around a small group of technologies is expected to intensify with solar-based technologies predicted to become more important. This paper challenges the dominant technical rationality in the literature that technical efficiency and cost benefits are the primary drivers for technology selection. These drivers play an important role but one which is mediated by the logic of maintaining the SDPTs of the house builders. This emphasises the need for construction diffusion of innovation theory to be problematized and developed within the context of business and market regimes constrained and reproduced by resilient technological trajectories.

Dysregulation of REST-regulated coding and non-coding RNAs in a cellular model of Huntington's disease

Huntingtin (Htt) protein interacts with many transcriptional regulators, with widespread disruption to the transcriptome in Huntington's disease (HD) brought about by altered interactions with the mutant Htt (muHtt) protein. Repressor Element-1 Silencing Transcription Factor (REST) is a repressor whose association with Htt in the cytoplasm is disrupted in HD, leading to increased nuclear REST and concomitant repression of several neuronal-specific genes, including brain-derived neurotrophic factor (Bdnf). Here, we explored a wide set of HD dysregulated genes to identify direct REST targets whose expression is altered in a cellular model of HD but that can be rescued by knock-down of REST activity. We found many direct REST target genes encoding proteins important for nervous system development, including a cohort involved in synaptic transmission, at least two of which can be rescued at the protein level by REST knock-down. We also identified several microRNAs (miRNAs) whose aberrant repression is directly mediated by REST, including miR-137, which has not previously been shown to be a direct REST target in mouse. These data provide evidence of the contribution of inappropriate REST-mediated transcriptional repression to the widespread changes in coding and non-coding gene expression in a cellular model of HD that may affect normal neuronal function and survival.