Fyn Kinase regulates GluN2B subunit-dominant NMDA receptors in human induced pluripotent stem cell-derived neurons

NMDA receptor (NMDAR)-mediated fast excitatory neurotransmission is implicated in a broad range of physiological and pathological processes in the mammalian central nervous system. The function and regulation of NMDARs have been extensively studied in neurons from rodents and other non-human species, and in recombinant expression systems. Here, we investigated human NMDARs in situ by using neurons produced by directed differentiation of human induced pluripotent stem cells (iPSCs). The resultant cells showed electrophysiological characteristics demonstrating that they are bona fide neurons. In particular, human iPSC-derived neurons expressed functional ligand-gated ion channels, including NMDARs, AMPA receptors, GABAA receptors, as well as glycine receptors. Pharmacological and electrophysiological properties of NMDAR-mediated currents indicated that these were dominated by receptors containing GluN2B subunits. The NMDAR currents were suppressed by genistein, a broad-spectrum tyrosine kinase inhibitor. The NMDAR currents were also inhibited by a Fyn-interfering peptide, Fyn(39-57), but not a Src-interfering peptide, Src(40-58). Together, these findings are the first evidence that tyrosine phosphorylation regulates the function of NMDARs in human iPSC-derived neurons. Our findings provide a basis for utilizing human iPSC-derived neurons in screening for drugs targeting NMDARs in neurological disorders

Potentiation of Synaptic GluN2B NMDAR Currents by Fyn Kinase Is Gated through BDNF-Mediated Disinhibition in Spinal Pain Processing

In chronic pain states, the neurotrophin brain-derived neurotrophic factor (BDNF) transforms the output of lamina I spinal neurons by decreasing synaptic inhibition. Pain hypersensitivity also depends on N-methyl-D-aspartate receptors (NMDARs) and Src-family kinases, but the locus of NMDAR dysregulation remains unknown. Here, we show that NMDAR-mediated currents at lamina I synapses are potentiated in a peripheral nerve injury model of neuropathic pain. We find that BDNF mediates NMDAR potentiation through activation of TrkB and phosphorylation of the GluN2B subunit by the Src-family kinase Fyn. Surprisingly, we find that Cl−-dependent disinhibition is necessary and sufficient to prime potentiation of synaptic NMDARs by BDNF. Thus, we propose that spinal pain amplification is mediated by a feedforward mechanism whereby loss of inhibition gates the increase in synaptic excitation within individual lamina I neurons. Given that neither disinhibition alone nor BDNF-TrkB signaling is sufficient to potentiate NMDARs, we have discovered a form of molecular coincidence detection in lamina I neurons

Trans-disciplinary research in synthesis of grass pollen aerobiology and its importance for respiratory health in Australasia

© 2015 Published by Elsevier B.V. Grass pollen is a major trigger for allergic rhinitis and asthma, yet little is known about the timing and levels of human exposure to airborne grass pollen across Australasian urban environments. The relationships between environmental aeroallergen exposure and allergic respiratory disease bridge the fields of ecology, aerobiology, geospatial science and public health. The Australian Aerobiology Working Group comprised of experts in botany, palynology, biogeography, climate change science, plant genetics, biostatistics, ecology, pollen allergy, public and environmental health, and medicine, was established to systematically source, collate and analyse atmospheric pollen concentration data from 11 Australian and six New Zealand sites. Following two week-long workshops, post-workshop evaluations were conducted to reflect upon the utility of this analysis and synthesis approach to address complex multidisciplinary questions. This Working Group described i) a biogeographically dependent variation in airborne pollen diversity, ii) a latitudinal gradient in the timing, duration and number of peaks of the grass pollen season, and iii) the emergence of new methodologies based on trans-disciplinary synthesis of aerobiology and remote sensing data. Challenges included resolving methodological variations between pollen monitoring sites and temporal variations in pollen datasets. Other challenges included "marrying" ecosystem and health sciences and reconciling divergent expert opinion. The Australian Aerobiology Working Group facilitated knowledge transfer between diverse scientific disciplines, mentored students and early career scientists, and provided an uninterrupted collaborative opportunity to focus on a unifying problem globally. The Working Group provided a platform to optimise the value of large existing ecological datasets that have importance for human respiratory health and ecosystems research. Compilation of current knowledge of Australasian pollen aerobiology is a critical first step towards the management of exposure to pollen in patients with allergic disease and provides a basis from which the future impacts of climate change on pollen distribution can be assessed and monitored

The 2020 special report of the MJA–Lancet Countdown on health and climate change: lessons learnt from Australia's "Black Summer"

The MJA-Lancet Countdown on health and climate change was established in 2017, and produced its first Australian national assessment in 2018 and its first annual update in 2019. It examines indicators across five broad domains: climate change impacts, exposures and vulnerability; adaptation, planning and resilience for health; mitigation actions and health co-benefits; economics and finance; and public and political engagement. In the wake of the unprecedented and catastrophic 2019-20 Australian bushfire season, in this special report we present the 2020 update, with a focus on the relationship between health, climate change and bushfires, highlighting indicators that explore these linkages. In an environment of continuing increases in summer maximum temperatures and heatwave intensity, substantial increases in both fire risk and population exposure to bushfires are having an impact on Australia's health and economy. As a result of the "Black Summer" bushfires, the monthly airborne particulate matter less than 2.5 μm in diameter (PM2.5 ) concentrations in New South Wales and the Australian Capital Territory in December 2019 were the highest of any month in any state or territory over the period 2000-2019 at 26.0 μg/m3 and 71.6 μg/m3 respectively, and insured economic losses were $2.2 billion. We also found growing awareness of and engagement with the links between health and climate change, with a 50% increase in scientific publications and a doubling of newspaper articles on the topic in Australia in 2019 compared with 2018. However, despite clear and present need, Australia still lacks a nationwide adaptation plan for health. As Australia recovers from the compounded effects of the bushfires and the coronavirus disease 2019 (COVID-19) pandemic, the health profession has a pivotal role to play. It is uniquely suited to integrate the response to these short term threats with the longer term public health implications of climate change, and to argue for the economic recovery from COVID-19 to align with and strengthen Australia's commitments under the Paris Agreement

Predictive feedback control and Fitts' law

Fitts’ law is a well established empirical formula, known for encapsulating the “speed-accuracy trade-off”. For discrete, manual movements from a starting location to a target, Fitts’ law relates movement duration to the distance moved and target size. The widespread empirical success of the formula is suggestive of underlying principles of human movement control. There have been previous attempts to relate Fitts’ law to engineering-type control hypotheses and it has been shown that the law is exactly consistent with the closed-loop step-response of a time-delayed, first-order system. Assuming only the operation of closed-loop feedback, either continuous or intermittent, this paper asks whether such feedback should be predictive or not predictive to be consistent with Fitts law. Since Fitts’ law is equivalent to a time delay separated from a first-order system, known control theory implies that the controller must be predictive. A predictive controller moves the time-delay outside the feedback loop such that the closed-loop response can be separated into a time delay and rational function whereas a non- predictive controller retains a state delay within feedback loop which is not consistent with Fitts’ law. Using sufficient parameters, a high-order non-predictive controller could approximately reproduce Fitts’ law. However, such high-order, “non-parametric” controllers are essentially empirical in nature, without physical meaning, and therefore are conceptually inferior to the predictive controller. It is a new insight that using closed-loop feedback, prediction is required to physically explain Fitts’ law. The implication is that prediction is an inherent part of the “speed-accuracy trade-off”

Differences in grass pollen allergen exposure across Australia

© 2015 The Authors © 2015 Public Health Association of Australia. Objective: Allergic rhinitis and allergic asthma are important chronic diseases posing serious public health issues in Australia with associated medical, economic, and societal burdens. Pollen are significant sources of clinically relevant outdoor aeroallergens, recognised as both a major trigger for, and cause of, allergic respiratory diseases. This study aimed to provide a national, and indeed international, perspective on the state of Australian pollen data using a large representative sample. Methods: Atmospheric grass pollen concentration is examined over a number of years within the period 1995 to 2013 for Brisbane, Canberra, Darwin, Hobart, Melbourne, and Sydney, including determination of the 'clinical' grass pollen season and grass pollen peak. Results: The results of this study describe, for the first time, a striking spatial and temporal variability in grass pollen seasons in Australia, with important implications for clinicians and public health professionals, and the Australian grass pollen-allergic community. Conclusions: These results demonstrate that static pollen calendars are of limited utility and in some cases misleading. This study also highlights significant deficiencies and limitations in the existing Australian pollen monitoring and data. Implications: Establishment of an Australian national pollen monitoring network would help facilitate advances in the clinical and public health management of the millions of Australians with asthma and allergic rhinitis

Impact of meteorological variation on hospital visits of patients with tree pollen allergy

<p>Abstract</p> <p>Background</p> <p>Climate change could affect allergic diseases, especially due to pollen. However, there has been no epidemiologic study to demonstrate the relationship between meteorological factors, pollen, and allergic patients. We aimed to investigate the association between meteorological variations and hospital visits of patients with tree pollen allergy.</p> <p>Methods</p> <p>The study subjects were adult patients who received skin prick tests between April and July from 1999 to 2008. We reviewed the medical records for the test results of 4,715 patients. Patients with tree pollen allergy were defined as those sensitized to more than 1 of 12 tree pollen allergens. We used monthly means of airborne tree pollen counts and meteorological factors: maximum/average/minimum temperature, relative humidity, and precipitation. We analyzed the correlations between meteorological variations, tree pollen counts, and the patient numbers. Multivariable logistic regression analyses were used to investigate the associations between meteorological factors and hospital visits of patients.</p> <p>Results</p> <p>The minimum temperature in March was significantly and positively correlated with tree pollen counts in March/April and patient numbers from April through July. Pollen counts in March/April were also correlated with patient numbers from April through July. After adjusting for confounders, including air pollutants, there was a positive association between the minimum temperature in March and hospital visits of patients with tree pollen allergy from April to July(odds ratio, 1.14; 95% CI 1.03 to 1.25).</p> <p>Conclusions</p> <p>Higher temperatures could increase tree pollen counts, affecting the symptoms of patients with tree pollen allergy, thereby increasing the number of patients visiting hospitals.</p

Emerging advances in biosecurity to underpin human, animal, plant, and ecosystem health

One Biosecurity is an interdisciplinary approach to policy and research that builds on the interconnections between human, animal, plant, and ecosystem health to effectively prevent and mitigate the impacts of invasive alien species. To support this approach requires that key cross-sectoral research innovations be identified and prioritized. Following an interdisciplinary horizon scan for emerging research that underpins One Biosecurity, four major interlinked advances were identified: implementation of new surveillance technologies adopting state-of-the-art sensors connected to the Internet of Things, deployable handheld molecular and genomic tracing tools, the incorporation of wellbeing and diverse human values into biosecurity decision-making, and sophisticated socio-environmental models and data capture. The relevance and applicability of these innovations to address threats from pathogens, pests, and weeds in both terrestrial and aquatic ecosystems emphasize the opportunity to build critical mass around interdisciplinary teams at a global scale that can rapidly advance science solutions targeting biosecurity threats

Expression and DNA methylation of TNF, IFNG and FOXP3 in colorectal cancer and their prognostic significance.

BACKGROUND: Colorectal cancer (CRC) progression is associated with suppression of host cell-mediated immunity and local immune escape mechanisms. Our aim was to assess the immune function in terms of expression of TNF, IFNG and FOXP3 in CRC. METHODS: Sixty patients with CRC and 15 matched controls were recruited. TaqMan quantitative PCR and methylation-specific PCR was performed for expression and DNA methylation analysis of TNF, IFNG and FOXP3. Survival analysis was performed over a median follow-up of 48 months. RESULTS: TNF was suppressed in tumour and IFNG was suppressed in peripheral blood mononuclear cells (PBMCs) of patients with CRC. Tumours showed enhanced expression of FOXP3 and was significantly higher when tumour size was >38 mm (median tumour size; P=0.006, Mann-Whitney U-test). Peripheral blood mononuclear cell IFNG was suppressed in recurrent CRC (P=0.01). Methylated TNFpromoter (P=0.003) and TNFexon1 (P=0.001) were associated with significant suppression of TNF in tumours. Methylated FOXP3cpg was associated with significant suppression of FOXP3 in both PBMC (P=0.018) and tumours (P=0.010). Reduced PBMC FOXP3 expression was associated with significantly worse overall survival (HR=8.319, P=0.019). CONCLUSIONS: We have detected changes in the expression of immunomodulatory genes that could act as biomarkers for prognosis and future immunotherapeutic strategies

Natural evolution of desmoplastic fibroblastoma on magnetic resonance imaging: a case report

<p>Abstract</p> <p>Introduction</p> <p>Desmoplastic fibroblastoma (collagenous fibroma) is a recently described tumor thought to arise predominantly from subcutaneous tissue or skeletal muscle. The natural evolution of this tumor on magnetic resonance imaging has never been described, to the best of our knowledge. We herein report a case of desmoplastic fibroblastoma arising in the thigh and show the longitudinal magnetic resonance imaging findings.</p> <p>Case presentation</p> <p>A 60-year-old Japanese man presented with swelling of the medial side of his right thigh, and he complained of nighttime pain and slight tenderness. Magnetic resonance imaging demonstrated a 4 × 4 cm mass in the right thigh. Open biopsy was performed. The mass was diagnosed histologically as a benign fibrous tumor, and we maintained follow-up without surgical therapy. After one year, magnetic resonance imaging showed an increase in tumor size to 4 × 5 cm, but the histologic findings were the same as those obtained one year earlier. Resection was performed with narrow surgical margins. Pathologic diagnosis was desmoplastic fibroblastoma. Two years after surgery, the patient is free from pain and shows no signs or symptoms of recurrence.</p> <p>Conclusion</p> <p>The natural evolution of desmoplastic fibroblastoma is characterized by no changes in patterns on magnetic resonance imaging despite increasing size. This finding is clinically helpful for distinguishing desmoplastic fibroblastoma with increasing pain from the desmoid tumor.</p