Nonconservation of the Valley Density and Its Implications for the Observation of the Valley Hall Effect.

We show that the conservation of the valley density in multivalley insulators is broken in an unexpected way by the electric field that drives the valley Hall effect. This implies that time-reversal-invariant fully gapped insulators, in which no bulk or edge state crosses the Fermi level, can support a valley Hall current in the bulk and yet show no valley density accumulation at the edges. Thus, the valley Hall effect cannot be observed in such systems. If the system is not fully gapped then valley density accumulation at the edges is possible. The accumulation has no contribution from undergap states and can be expressed as a Fermi surface average, for which we derive an explicit formula. We demonstrate the theory by calculating the valley density accumulations in an archetypical valley-Hall insulator: a gapped graphene nanoribbon. Surprisingly, we discover that a net valley density polarization is dynamically generated for certain edge terminations.

Sex-Related Microglial Perturbation Is Related to Mitochondrial Changes in a Model of Alzheimer's Disease.

Many studies implicate microglia in the pathogenesis of Alzheimer's disease (AD) but precisely how these cells make their impact has not been determined to date. One contributory factor is likely to be the enhanced production of inflammatory mediators and it is now known that microglia with this secretory phenotype exhibit other adaptations including in their morphology, function, and metabolism. AD, like many neurological disorders, demonstrates a sex bias and recent evidence indicates that the sexual dimorphism in microglial function, which has been recognized for many years in early development, persists into adulthood and aging. Here, we demonstrate sex-related differences in microglia from post mortem tissue of male and female AD patients and a marked increase in the number of dystrophic and rod-shaped microglia in tissue from female AD patients compared with males. Furthermore, there was an increase in iron-laden microglia in tissue from female AD patients and this has been reported to reflect mitochondrial changes. To address this further, we assessed changes in microglia from male and female APP/PS1 mice and demonstrate that iron accumulation in microglia is increased to a greater extent in tissue prepared from females compared with males. This was associated with altered expression of genes coding for proteins that modulate mitochondrial function. The findings suggest that sex-related differences in the severity and perhaps incidence of AD may, at least in part, arise from sexual dimorphism in microglia.

The Modulatory Effects of DMF on Microglia in Aged Mice Are Sex-Specific.

There is a striking sex-related difference in the prevalence of many neurodegenerative diseases, highlighting the need to consider whether treatments may exert sex-specific effects. A change in microglial activation state is a common feature of several neurodegenerative diseases and is considered to be a key factor in driving the inflammation that characterizes these conditions. Among the changes that have been described is a switch in microglial metabolism towards glycolysis which is associated with production of inflammatory mediators and reduced function. Marked sex-related differences in microglial number, phenotype and function have been described in late embryonic and early postnatal life in rodents and some reports suggest that sexual dimorphism extends into adulthood and age and, in models of Alzheimer's disease, the changes are more profound in microglia from female, compared with male, mice. Dimethyl fumarate (DMF) is a fumaric acid ester used in the treatment of psoriasis and relapsing remitting multiple sclerosis and, while its mechanism of action is unclear, it possesses anti-inflammatory and anti-oxidant properties and also impacts on cell metabolism. Here we treated 16-18-month-old female and male mice with DMF for 1 month and assessed its effect on microglia. The evidence indicates that it exerted sex-specific effects on microglial morphology and metabolism, reducing glycolysis only in microglia from female mice. The data suggest that this may result from its ability to inactivate glyceraldehyde-3-phosphate dehydrogenase (GAPDH).

Microglial metabolism is a pivotal factor in sexual dimorphism in Alzheimer's disease.

Age and sex are major risk factors in Alzheimer's disease (AD) with a higher incidence of the disease in females. Neuroinflammation, which is a hallmark of AD, contributes to disease pathogenesis and is inexorably linked with inappropriate microglial activation and neurodegeneration. We investigated sex-related differences in microglia in APP/PS1 mice and in post-mortem tissue from AD patients. Changes in genes that are indicative of microglial activation were preferentially increased in cells from female APP/PS1 mice and cells from males and females were morphological, metabolically and functionally distinct. Microglia from female APP/PS1 mice were glycolytic and less phagocytic and associated with increased amyloidosis whereas microglia from males were amoeboid and this was also the case in post-mortem tissue from male AD patients, where plaque load was reduced. We propose that the sex-related differences in microglia are likely to explain, at least in part, the sexual dimorphism in AD.

Planning for the health impacts of climate change: Flooding, private groundwater contamination and waterborne infection - A cross-sectional study of risk perception, experience and behaviours in the Republic of Ireland.

The frequency and severity of flooding events will increase over the coming decades due to global climate change. While close attention has typically been paid to infrastructural and environmental outcomes of flood events, the potential adverse human health consequences associated with post-event consumption from private groundwater sources have received minimal attention, leading to a poor understanding of private well users' preparedness and the drivers of positive behavioural adoption. The current study sought to quantify the capacity of private well users to cope with flood-triggered contamination risks and identify the social psychological determinants of proactive attitudes in the Republic of Ireland, using a cross-sectional questionnaire incorporating two distinct models of health behaviour, the Health Belief Model and Risk-Attitude-Norms-Ability-Self Regulation model. Adoption of healthy behaviours prior to flooding was evaluated with respect to respondents' risk exposure, risk experience and risk perception, in addition to systematic supply stewardship under normal conditions. Associations between adoption of protective behaviours and perception, experience and socio-demographic factors were evaluated through multinomial and multiple logistic regressions, while a multi-model inferential approach was employed with the predictors of health behaviour models. Findings suggest that floods are not considered likely to occur, nor were respondents worried about their occurrence, with 72.5% of respondents who reported previous flooding experience failing to adopt protective actions. Prior experience of well water contamination increased adoption of proactive attitudes when flooding occurred (+47%), with a failure to adopt healthy behaviours higher among rural non-agricultural residents (136%). Low levels of preparedness to deal with flood-related contamination risks are a side-effect of the general lack of appropriate well stewardship under normal conditions; just 10.1% of respondents adopted both water treatment and frequent testing, in concurrence with limited risk perception and poor awareness of the nexus between risk factors (e.g. floods, contamination sources) and groundwater quality. Perceived risk, personal norms and social norms were the best predictors of protective behaviour adoption and should be considered when developing future awareness campaigns.

Acute neuroinflammation, sickness behavior and working memory responses to acute systemic LPS challenge following noradrenergic lesion in mice.

Locus coeruleus (LC)-derived noradrenaline is important in cognition and decreases with age, but the impact of prior noradrenaline deficiency on vulnerability to inflammation-induced acute cognitive dysfunction is unclear. Here we assessed whether noradrenergic depletion, in female mice, impacted upon inflammation, locomotor activity and working memory directly after acute systemic immune challenge with bacterial lipopolysaccharide (LPS), a paradigm we have previously used to capture delirium-like acute cognitive deficits. Mice received 2 doses of the LC-selective noradrenergic toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 50 mg/kg i.p.) and were challenged, 2 weeks later, with LPS (100 µg/kg i.p.). DSP-4 dramatically reduced noradrenaline concentrations and tyrosine hydroxylase-positive afferents in the frontal cortex and hippocampus. This did not significantly alter numbers of Pu.1-positive microglia, Iba1-positive microglial morphology or mRNA expression of microglia-associated gene transcripts (Tyrobp, Sall1, Cd68, Sra2, Clec7a) in the hippocampus or frontal cortex and produced modest reductions in Cx3cr1 and P2ry12. LPS induced blood and brain cytokine levels, cFOS activation and locomotor responses that were highly similar in DSP-4- and vehicle-treated mice, although LPS-induced plasma TNF-α was significantly reduced in those treated with DSP-4. Importantly, prior noradrenergic depletion did not predispose to LPS-induced T-maze working memory deficits. The data demonstrate that significant depletion of noradrenaline in the hippocampus and frontal cortex does not prompt acutely exaggerated neuroinflammation or leave the brain vulnerable to acute, transient working memory deficits upon low dose LPS challenge. These findings have implications for our understanding of the impact of systemic inflammation on the aging and vulnerable brain during septic encephalopathy and delirium.

Gender-Related Differences in Flood Risk Perception and Behaviours among Private Groundwater Users in the Republic of Ireland.

Extreme weather events including flooding can have severe personal, infrastructural, and economic consequences, with recent evidence pointing to surface flooding as a pathway for the microbial contamination of private groundwater supplies. There is a pressing need for increasingly focused information and awareness campaigns to highlight the risks posed by extreme weather events and appropriate subsequent post-event actions. To date, little is known about the presence, directionality or magnitude of gender-related differences regarding flood risk awareness and behaviour among private groundwater users, a particularly susceptible sub-population due to an overarching paucity of infrastructural regulation across many regions. The current study investigated gender-related differences in flood risk perception and associated mitigation behaviours via a cross-sectional, national survey of 405 (168 female, 237 male) private groundwater supply users. The developed survey instrument assessed socio-demographic profile, previous flood experience, experiential and conjectural health behaviours (contingent on previous experience), and Risk, Attitude, Norms, Ability, Self-regulation (RANAS) framework questions. Statistically significant gender differences were found between both 'Norm-Descriptive' and 'Ability-Self-efficacy' RANAS elements (p < 0.05). Female respondents reported a lower level of awareness of the need for post-flood action(s) (8.9% vs. 16.5%), alongside a perceived "lack of information" as a reason for not testing their domestic well (4.9% vs. 11.5%). Conversely, male respondents were more likely to report awareness of their well location in relation to possible contamination sources (96.6% vs. 89.9%) and awareness of previous water testing results (98.9% vs. 93.0%). Gender-related gaps exist within the studied private groundwater reliant cohort, a sub-population which has to date remained under-studied within the context of climate change and extreme weather events. Accordingly, findings suggest that gender-focused communication and education may represent an effective tool for protecting current and future generations of global groundwater users.

Pharmacological targeting of ß2 -adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease.

BACKGROUND AND PURPOSE: Chronic inflammation may play a role in the pathogenesis of Parkinson's disease (PD). Noradrenaline is an endogenous neurotransmitter with anti-inflammatory properties. In the present investigation, we assessed the immunomodulatory and neuroprotective efficacy of pharmacologically targeting the CNS noradrenergic system in a rat model of PD. EXPERIMENTAL APPROACH: The impact of treatment with the ß2 -adrenoceptor agonists clenbuterol and formoterol was assessed in the intranigral LPS rat model of PD. The immunomodulatory potential of formoterol to influence the CNS response to systemic inflammation was also assessed. KEY RESULTS: LPS-induced deficits in motor function (akinesia and forelimb-use asymmetry) and nigrostriatal dopamine loss were rescued by both agents. Treatment with the noradrenaline reuptake inhibitor atomoxetine reduced striatal dopamine loss and motor deficits following intranigral LPS injection. Co-treatment with the ß2 -adrenoceptor antagonist ICI 118,551 attenuated the protective effects of atomoxetine. Systemic LPS challenge exacerbated reactive microgliosis, IL-1ß production, dopamine cell loss in the substantia nigra, nerve terminal degeneration in the striatum, and associated motor impairments in animals that previously received intranigral LPS. This exacerbation was attenuated by formoterol treatment. CONCLUSION AND IMPLICATIONS: The results indicate that pharmacologically targeting ß2 -adrenoceptors has the propensity to regulate the neuroinflammatory phenotype in vivo and may be a potential neuroprotective strategy where inflammation contributes to the progression of dopaminergic neurodegeneration. In accordance with this, clinical agents such as ß2 -adrenoceptor agonists may prove useful as immunomodulatory agents in the treatment of neurodegenerative conditions associated with brain inflammation.

L-alpha-aminoadipic acid restricts dopaminergic neurodegeneration and motor deficits in an inflammatory model of Parkinson's disease in male rats.

Neuroinflammation is a contributory factor underlying the progressive nature of dopaminergic neuronal loss within the substantia nigra (SN) of Parkinson's disease (PD) patients, albeit the role of astrocytes in this process has been relatively unexplored to date. Here, we aimed to investigate the impact of midbrain astrocytic dysfunction in the pathophysiology of intra-nigral lipopolysaccharide (LPS)-induced experimental Parkinsonism in male Wistar rats via simultaneous co-injection of the astrocytic toxin L-alpha-aminoadipic acid (L-AAA). Simultaneous intra-nigral injection of L-AAA attenuated the LPS-induced loss of tyrosine hydroxylase-positive (TH+ ) dopamine neurons in the SNpc and suppressed the affiliated degeneration of TH+ dopaminergic nerve terminals in the striatum. L-AAA also repressed LPS-induced nigrostriatal dopamine depletion and provided partial protection against ensuing motor dysfunction. L-AAA abrogated intra-nigral LPS-induced glial fibrillary acidic protein-positive (GFAP+ ) reactive astrogliosis and attenuated the LPS-mediated increases in nigral S100ß expression levels in a time-dependent manner, findings which were associated with reduced ionized calcium binding adaptor molecule 1-positive (Iba1+ ) microgliosis, thus indicating a role for reactive astrocytes in sustaining microglial activation at the interface of dopaminergic neuronal loss in response to an immune stimulus. These results indicate that midbrain astrocytic dysfunction restricts the development of dopaminergic neuropathology and motor impairments in rats, highlighting reactive astrocytes as key contributors in inflammatory associated degeneration of the nigrostriatal tract.

Targeting the noradrenergic system for anti-inflammatory and neuroprotective effects: implications for Parkinson's disease.

Degeneration of the locus coeruleus noradrenergic system is thought to play a key role in the pathogenesis of Parkinson's disease (PD), whereas pharmacological approaches to increase noradrenaline bioavailability may provide neuroprotection. Noradrenaline inhibits microglial activation and suppresses pro-inflammatory mediator production (e.g., tumor necrosis factor-α, interleukin-1ß & inducible nitric oxide synthase activity), thus limiting the cytotoxicity of midbrain dopaminergic neurons in response to an inflammatory stimulus. Neighbouring astrocyte populations promote a neurotrophic environment in response to ß2-adrenoceptor (ß2-AR) stimulation via the production of growth factors (e.g., brain derived neurotrophic factor, cerebral dopamine neurotrophic factor & glial cell derived neurotrophic factor which have shown promising neuroprotective and neuro-restorative effects in the nigrostriatal dopaminergic system. More recent findings have demonstrated a role for the ß2-AR in down-regulating expression levels of the human α-synuclein gene SNCA and relative α-synuclein protein abundance. Given that α-synuclein is a major protein constituent of Lewy body pathology, a hallmark neuropathological feature in Parkinson's disease, these findings could open up new avenues for pharmacological intervention strategies aimed at alleviating the burden of α-synucleinopathies in the Parkinsonian brain. In essence, the literature reviewed herein supports our hypothesis of a tripartite neuroprotective role for noradrenaline in combating PD-related neuropathology and motor dysfunction via (1) inhibiting nigral microglial activation & pro-inflammatory mediator production, (2) promoting the synthesis of neurotrophic factors from midbrain astrocytes and (3) downregulating α-synuclein gene expression and protein abundance in a ß2-AR-dependent manner. Thus, taken together, either pharmacologically enhancing extra-synaptic noradrenaline bioavailability or targeting glial ß2-ARs directly makes itself as a promising treatment option aimed at slowing/halting PD progression.

The ß2-adrenoceptor agonist clenbuterol reduces the neuroinflammatory response, neutrophil infiltration and apoptosis following intra-striatal IL-1ß administration to rats.

OBJECTIVES: Clenbuterol is a brain penetrant ß2-adrenoceptor agonist with anti-inflammatory and putative neuroprotective properties. In the present investigation, the effect of clenbuterol was assessed in a rat model of acute brain injury induced by intra-striatal administration of the pro-inflammatory cytokine IL-1ß. METHODS: Clenbuterol (0.5 mg/kg; i.p.) was administered one hour prior to stereotactically delivered IL-1ß (100 ng) into the striatum. Four hours postinjection, rats were anesthetized, blood samples were collected for circulating cytokine and chemokine analysis, and the ipsilateral striatum and liver tissue were harvested for mRNA expression analysis of target genes. RESULTS: Intrastriatal IL-1ß provoked an inflammatory response with increased expression of IL-1ß and the pro-inflammatory cytokine TNF-α. TNF-α expression was also increased in the liver and circulating concentrations of the chemokine cytokine-induced neutrophil chemoattractant 1 (CINC-1) were raised in response to intrastriatal IL-1ß administration. The striatal response was accompanied by NFκB activation and 24 hours postinjection, increased immunoreactivity of the neutrophil marker MBS-2, indicative of cell infiltration and increased TUNEL staining, a cell marker of apoptosis. Treatment with clenbuterol attenuated all IL-1ß-induced changes in the striatum including MBS-2 immunoreactivity and TUNEL + staining. Clenbuterol also attenuated IL-1ß-induced expression of TNF-α in the liver and the increase in circulating CINC-1 concentrations. CONCLUSIONS: The results provide evidence that clenbuterol elicits anti-inflammatory effects, suppresses the peripheral acute phase response and reduces the infiltration of neutrophils and apoptotic response to acute IL-1ß-induced brain injury. Suppression of both the central and peripheral response following clenbuterol administration may contribute to its protective properties following brain injury.

Treatment with the noradrenaline re-uptake inhibitor atomoxetine alone and in combination with the α2-adrenoceptor antagonist idazoxan attenuates loss of dopamine and associated motor deficits in the LPS inflammatory rat model of Parkinson's disease.

The impact of treatment with the noradrenaline (NA) re-uptake inhibitor atomoxetine and the α2-adrenoceptor (AR) antagonist idazoxan in an animal model of Parkinson's disease (PD) was assessed. Concurrent systemic treatment with atomoxetine and idazoxan, a combination which serves to enhance the extra-synaptic availability of NA, exerts anti-inflammatory and neuroprotective effects following delivery of an inflammatory stimulus, the bacterial endotoxin, lipopolysaccharide (LPS) into the substantia nigra. Lesion-induced deficits in motor function (akinesia, forelimb-use asymmetry) and striatal dopamine (DA) loss were rescued to varying degrees depending on the treatment. Treatment with atomoxetine following LPS-induced lesion to the substantia nigra, yielded a robust anti-inflammatory effect, suppressing microglial activation and expression of the pro-inflammatory cytokine TNF-α whilst increasing the expression of neurotrophic factors. Furthermore atomoxetine treatment prevented loss of tyrosine hydroxylase (TH) positive nigral dopaminergic neurons and resulted in functional improvements in motor behaviours. Atomoxetine alone was sufficient to achieve most of the observed effects. In combination with idazoxan, an additional improvement in the impairment of contralateral limb use 7 days post lesion and a reduction in amphetamine-mediated rotational asymmetry 14 days post-lesion was observed, compared to atomoxetine or idazoxan treatments alone. The results indicate that increases in central NA tone has the propensity to regulate the neuroinflammatory phenotype in vivo and may act as an endogenous neuroprotective mechanism where inflammation contributes to the progression of DA loss. In accordance with this, the clinical use of agents such as NA re-uptake inhibitors and α2-AR antagonists may prove useful in enhancing the endogenous neuroimmunomodulatory potential of NA in conditions associated with brain inflammation.

The framing of two major flood episodes in the Irish print news media: Implications for societal adaptation to living with flood risk.

Societal adaptation to flooding is a critical component of contemporary flood policy. Using content analysis, this article identifies how two major flooding episodes (2009 and 2014) are framed in the Irish broadsheet news media. The article considers the extent to which these frames reflect shifts in contemporary flood policy away from protection towards risk management, and the possible implications for adaptation to living with flood risk. Frames help us make sense of the social world, and within the media, framing is an essential tool for communication. Five frames were identified: flood resistance and structural defences, politicisation of flood risk, citizen as risk manager, citizen as victim and emerging trade-offs. These frames suggest that public debates on flood management do not fully reflect shifts in contemporary flood policy, with negative implications for the direction of societal adaptation. Greater discussion is required on the influence of the media on achieving policy objectives.

The Impact of Perceived Flood Exposure on Flood-Risk Perception: The Role of Distance.

Natural hazards, such as major flood events, are occurring with increasing frequency and inflicting increasing levels of financial damages upon affected communities. The experience of such major flood events has brought about a significant change in attitudes to flood-risk management, with a shift away from built engineering solutions alone towards a more multifaceted approach. Europe's experience with damaging flood episodes provided the impetus for the introduction of the European Floods Directive, requiring the establishment of flood-risk management plans at the river-basin scale. The effectiveness of such plans, focusing on prevention, protection, and preparedness, is dependent on adequate flood awareness and preparedness, and this is related to perception of flood risk. This is an important factor in the design and assessment of flood-risk management. Whilst there is a modern body of literature exploring flood perception issues, there have been few examples that explore its spatial manifestations. Previous literature has examined perceived and real distance to a hazard source (such as a river, nuclear facility, landfill, or incinerator, etc.), whereas this article advances the literature by including an objectively assessed measure of distance to a perceived flood zone, using a cognitive mapping methodology. The article finds that distance to the perceived flood zone (perceived flood exposure) is a crucial factor in determining flood-risk perception, both the cognitive and affective components. Furthermore, we find an interesting phenomenon of misperception among respondents. The article concludes by discussing the implications for flood-risk management.

Guerra, formação do estado e identidade nacional nas franjas do mundo Atlântico / Guerre, formation de l'état et identité nationale dans lês franges du monde Atlantique / War, state formation, and national identity on the fringes of the Atlantic world

This paper deals with the impact of war on state formation in Ireland and England, focusing on the period from 1590 to 1691, the key turning point for the future development of the state in both countries. War played a vital role, but in a number of different ways, including in the ideological sphere, in a complex process, rather than simply causing a long-term expansion in army size and subsequent growth of the state. The author further emphasizes the dynamic nature of the state itself.

Dans cet article, on étudie l'impact de la guerre sur la formation de l'État en Irlande et en Angleterre, surtout dans la période de 1590 à 1691, période-clé pour le développement de l'État dans ces deux pays. La guerre y a joué un rôle très important sous plusieurs formes, et en particulier dans la sphère idéologique, au long d'un processus très complexe, au-delà de son rôle d'expansion et d'augmentation des armées et de sa conséquence, la croissance de l'État, dont il faut souligner la nature dynamique.