TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain

Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders. Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation—imiquimod—to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour. Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity. Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response

Rapid motion adaptation reveals the temporal dynamics of spatiotemporal correlation between ON and OFF pathways

At the early stages of visual processing, information is processed by two major thalamic pathways encoding brightness increments (ON) and decrements (OFF). Accumulating evidence suggests that these pathways interact and merge as early as in primary visual cortex. Using regular and reverse-phi motion in a rapid adaptation paradigm, we investigated the temporal dynamics of within and across pathway mechanisms for motion processing. When the adaptation duration was short (188 ms), reverse-phi and regular motion led to similar adaptation effects, suggesting that the information from the two pathways are combined efficiently at early-stages of motion processing. However, as the adaption duration was increased to 752 ms, reverse-phi and regular motion showed distinct adaptation effects depending on the test pattern used, either engaging spatiotemporal correlation between the same or opposite contrast polarities. Overall, these findings indicate that spatiotemporal correlation within and across ON-OFF pathways for motion processing can be selectively adapted, and support those models that integrate within and across pathway mechanisms for motion processing

Increasing the simulation performance of large-scale evacuations using parallel computing techniques based on domain decomposition

Evacuation simulation has the potential to be used as part of a decision support system during large-scale incidents to provide advice to incident commanders. To be viable in these applications, it is essential that the simulation can run many times faster than real time. Parallel processing is a method of reducing run times for very large computational simulations by distributing the workload amongst a number of processors. This paper presents the development of a parallel version of the rule based evacuation simulation software buildingEXODUS using domain decomposition. Four Case Studies (CS) were tested using a cluster, consisting of 10 Intel Core 2 Duo (dual core) 3.16 GHz CPUs. CS-1 involved an idealised large geometry, with 20 exits, intended to illustrate the peak computational speed up performance of the parallel implementation, the population consisted of 100,000 agents; the peak computational speedup (PCS) was 14.6 and the peak real-time speedup (PRTS) was 4.0. CS-2 was a long area with a single exit area with a population of 100,000 agents; the PCS was 13.2 and the PRTS was 17.2. CS-3 was a 50 storey high rise building with a population of 8000/16,000 agents; the PCS was 2.48/4.49 and the PRTS was 17.9/12.9. CS-4 is a large realistic urban area with 60,000/120,000 agents; the PCS was 5.3/6.89 and the PRTS was 5.31/3.0. This type of computational performance opens evacuation simulation to a range of new innovative application areas such as real-time incident support, dynamic signage in smart buildings and virtual training environments

Extensive coronavirus-induced membrane rearrangements are not a determinant of pathogenicity

Positive-strand RNA (+RNA) viruses rearrange cellular membranes during replication, possibly in order to concentrate and arrange viral replication machinery for efficient viral RNA synthesis. Our previous work showed that in addition to the conserved coronavirus double membrane vesicles (DMVs), Beau-R, an apathogenic strain of avian Gammacoronavirus infectious bronchitis virus (IBV), induces regions of ER that are zippered together and tethered open-necked double membrane spherules that resemble replication organelles induced by other +RNA viruses. Here we compared structures induced by Beau-R with the pathogenic lab strain M41 to determine whether membrane rearrangements are strain dependent. Interestingly, M41 was found to have a low spherule phenotype. We then compared a panel of pathogenic, mild and attenuated IBV strains in ex vivo tracheal organ culture (TOC). Although the low spherule phenotype of M41 was conserved in TOCs, each of the other tested IBV strains produced DMVs, zippered ER and spherules. Furthermore, there was a significant correlation for the presence of DMVs with spherules, suggesting that these structures are spatially and temporally linked. Our data indicate that virus induced membrane rearrangements are fundamentally linked to the viral replicative machinery. However, coronavirus replicative apparatus clearly has the plasticity to function in different structural contexts

Modelling fast forms of visual neural plasticity using a modified second-order motion energy model

The Adelson-Bergen motion energy sensor is well established as the leading model of low-level visual motion sensing in human vision. However, the standard model cannot predict adaptation effects in motion perception. A previous paper Pavan et al.(Journal of Vision 10:1-17, 2013) presented an extension to the model which uses a first-order RC gain-control circuit (leaky integrator) to implement adaptation effects which can span many seconds, and showed that the extended model's output is consistent with psychophysical data on the classic motion after-effect. Recent psychophysical research has reported adaptation over much shorter time periods, spanning just a few hundred milliseconds. The present paper further extends the sensor model to implement rapid adaptation, by adding a second-order RC circuit which causes the sensor to require a finite amount of time to react to a sudden change in stimulation. The output of the new sensor accounts accurately for psychophysical data on rapid forms of facilitation (rapid visual motion priming, rVMP) and suppression (rapid motion after-effect, rMAE). Changes in natural scene content occur over multiple time scales, and multi-stage leaky integrators of the kind proposed here offer a computational scheme for modelling adaptation over multiple time scales. © 2014 Springer Science+Business Media New York

Sport and transgender people: a systematic review of the literature relating to sport participation and competitive sport policies

Background Whether transgender people should be able to compete in sport in accordance with their gender identity is a widely contested question within the literature and among sport organisations, fellow competitors and spectators. Owing to concerns surrounding transgender people (especially transgender female individuals) having an athletic advantage, several sport organisations place restrictions on transgender competitors (e.g. must have undergone gender-confirming surgery). In addition, some transgender people who engage in sport, both competitively and for leisure, report discrimination and victimisation. Objective To the authors’ knowledge, there has been no systematic review of the literature pertaining to sport participation or competitive sport policies in transgender people. Therefore, this review aimed to address this gap in the literature. Method Eight research articles and 31 sport policies were reviewed. Results In relation to sport-related physical activity, this review found the lack of inclusive and comfortable environments to be the primary barrier to participation for transgender people. This review also found transgender people had a mostly negative experience in competitive sports because of the restrictions the sport’s policy placed on them. The majority of transgender competitive sport policies that were reviewed were not evidence based. Conclusion Currently, there is no direct or consistent research suggesting transgender female individuals (or male individuals) have an athletic advantage at any stage of their transition (e.g. cross-sex hormones, gender-confirming surgery) and, therefore, competitive sport policies that place restrictions on transgender people need to be considered and potentially revised

A Recombinant Avian Infectious Bronchitis Virus Expressing a Heterologous Spike Gene Belonging to the 4/91 Serotype

We have shown previously that replacement of the spike (S) gene of the apathogenic IBV strain Beau-R with that from the pathogenic strain of the same serotype, M41, resulted in an apathogenic virus, BeauR-M41(S), that conferred protection against challenge with M41 [1]. We have constructed a recombinant IBV, BeauR-4/91(S), with the genetic backbone of Beau-R but expressing the spike protein of the pathogenic IBV strain 4/91(UK), which belongs to a different serogroup as Beaudette or M41. Similar to our previous findings with BeauR-M41(S), clinical signs observations showed that the S gene of the pathogenic 4/91 virus did not confer pathogenicity to the rIBV BeauR-4/91(S). Furthermore, protection studies showed there was homologous protection; BeauR-4/91(S) conferred protection against challenge with wild type 4/91 virus as shown by the absence of clinical signs, IBV RNA assessed by qRT-PCR and the fact that no virus was isolated from tracheas removed from birds primarily infected with BeauR-4/91(S) and challenged with IBV 4/91(UK). A degree of heterologous protection against M41 challenge was observed, albeit at a lower level

Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice

<div><p>Objective</p><p>Most anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1) not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1) develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a) in preeclampsia; 2) determine blood pressures in non-stressed conditions; and 3) develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP) monitoring.</p><p>Methods</p><p>Pregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD) 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11) or green fluorescent protein (GFP; n = 9) on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia.</p><p>Results</p><p>Ultrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18). Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3±51.7μg/mg vs. 19.3±5.6μg/mg, p = 4.4x10^-2; GD18). Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2x10^-2). Placental and fetal weights did not differ between the groups. One mouse with liver disease developed early-onset preeclampsia-like symptoms with intrauterine growth restriction (IUGR).</p><p>Conclusions</p><p>A mouse model of late-onset preeclampsia was developed with the overexpression of hsFlt-1-e15a, verifying the <i>in vivo</i> pathologic effects of this primate-specific, predominant placental sFlt-1 isoform. HsFlt-1-e15a induced early-onset preeclampsia-like symptoms associated with IUGR in a mouse with a liver disease. Our findings support that hsFlt-1-e15a is central to the terminal pathway of preeclampsia, and it can induce the full spectrum of symptoms in this obstetrical syndrome.</p></div

What do the australian black summer fires signify for the global fire crisis?

The 2019–20 Australian fire season was heralded as emblematic of the catastrophic harm wrought by climate change. Similarly extreme wildfire seasons have occurred across the globe in recent years. Here, we apply a pyrogeographic lens to the recent Australian fires to examine the range of causes, impacts and responses. We find that the extensive area burnt was due to extreme climatic circumstances. However, antecedent hazard reduction burns (prescribed burns with the aim of reducing fuel loads) were effective in reducing fire severity and house loss, but their effectiveness declined under extreme weather conditions. Impacts were disproportionately borne by socially disadvantaged regional communities. Urban populations were also impacted through prolonged smoke exposure. The fires produced large carbon emissions, burnt fire-sensitive ecosystems and exposed large areas to the risk of biodiversity decline by being too frequently burnt in the future. We argue that the rate of change in fire risk delivered by climate change is outstripping the capacity of our ecological and social systems to adapt. A multi-lateral approach is required to mitigate future fire risk, with an emphasis on reducing the vulnerability of people through a reinvigoration of community-level capacity for targeted actions to complement mainstream fire management capacity

Foot pressure distribution during walking in young and old adults

BACKGROUND: Measurement of foot pressure distribution (FPD) is clinically useful for evaluation of foot and gait pathologies. The effects of healthy aging on FPD during walking are not well known. This study evaluated FPD during normal walking in healthy young and elderly subjects. METHODS: We studied 9 young (30 ± 5.2 years), and 6 elderly subjects (68.7 ± 4.8 years). FPD was measured during normal walking speed using shoe insoles with 99 capacitive sensors. Measured parameters included gait phase characteristics, mean and maximum pressure and force, and relative load. Time-series measurements of each variable for all sensors were grouped into 9 anatomical masks. RESULTS: Elderly subjects had lower normalized maximum pressure for the medial and lateral calcaneal masks, and for all medial masks combined. In the medial calcaneus mask, the elderly group also had a lower absolute maximum and lower mean and normalized mean pressures and forces, compared to young subjects. Elderly subjects had lower maximum force and normalized maximum force and lower mean force and normalized mean forces in the medial masks as well. CONCLUSION: FPD differences between the young and elderly groups were confined to the calcaneus and hallux regions and to the medial side of the foot. In elderly subjects, weight bearing on the lateral side of the foot during heel touch and toe-off phases may affect stability during walking