Lectins offer new perspectives in the development of macrophage-targeted therapies for COPD/emphysema

We have previously shown that the defective ability of alveolar macrophages (AM) to phagocytose apoptotic cells (‘efferocytosis’) in chronic obstructive pulmonary disease/emphysema (COPD) could be therapeutically improved using the C-type lectin, mannose binding lectin (MBL), although the exact mechanisms underlying this effect are unknown. An S-type lectin, galectin-3, is also known to regulate macrophage phenotype and function, via interaction with its receptor CD98. We hypothesized that defective expression of galectin/CD98 would be associated with defective efferocytosis in COPD and that mechanisms would include effects on cytoskeletal remodeling and macrophage phenotype and glutathione (GSH) availability. Galectin-3 was measured by ELISA in BAL from controls, smokers and current/ex-smokers with COPD. CD98 was measured on AM using flow cytometry. We assessed the effects of galectin-3 on efferocytosis, CD98, GSH, actin polymerisation, rac activation, and the involvement of PI3K (using β-actin probing and wortmannin inhibition) in vitro using human AM and/or MH-S macrophage cell line. Significant decreases in BAL galectin-3 and AM CD98 were observed in BAL from both current- and ex-smoker COPD subjects vs controls. Galectin 3 increased efferocytosis via an increase in active GTP bound Rac1. This was confirmed with β-actin probing and the role of PI3K was confirmed using wortmannin inhibition. The increased efferocytosis was associated with increases in available glutathione and expression of CD98. We provide evidence for a role of airway lectins in the failed efferocytosis in COPD, supporting their further investigation as potential macrophage-targeted therapies.Violet R. Mukaro, Johan Bylund, Greg Hodge, Mark Holmes, Hubertus Jersmann, Paul N. Reynolds, Sandra Hodg

Arbuscular Mycorrhizal Fungi and Plant Chemical Defence : Effects of Colonisation on Aboveground and Belowground Metabolomes

Arbuscular mycorrhizal fungal (AMF) colonisation of plant roots is one of the most ancient and widespread interactions in ecology, yet the systemic consequences for plant secondary chemistry remain unclear. We performed the first metabolomic investigation into the impact of AMF colonisation by Rhizophagus irregularis on the chemical defences, spanning above- and below-ground tissues, in its host-plant ragwort (Senecio jacobaea). We used a non-targeted metabolomics approach to profile, and where possible identify, compounds induced by AMF colonisation in both roots and shoots. Metabolomics analyses revealed that 33 compounds were significantly increased in the root tissue of AMF colonised plants, including seven blumenols, plant-derived compounds known to be associated with AMF colonisation. One of these was a novel structure conjugated with a malonyl-sugar and uronic acid moiety, hitherto an unreported combination. Such structural modifications of blumenols could be significant for their previously reported functional roles associated with the establishment and maintenance of AM colonisation. Pyrrolizidine alkaloids (PAs), key anti-herbivore defence compounds in ragwort, dominated the metabolomic profiles of root and shoot extracts. Analyses of the metabolomic profiles revealed an increase in four PAs in roots (but not shoots) of AMF colonised plants, with the potential to protect colonised plants from below-ground organisms

AP2γ: a new player on adult hippocampal neurogenesis regulation

Since the recognition that the mammalian brain retains the ability to generate newborn neurons with functional relevance throughout life, the matrix of molecular regulators that govern adult neurogenesis has been the focus of much interest. In a recent study published in Molecular Psychiatry, we demonstrate Activating Protein 2γ (AP2γ), a transcription factor previously implicated in cell fate determination in the developing cortex, as a novel player in the regulation of glutamatergic neurogenesis in the adult hippocampus. Using distinct experimental approaches, we showed that AP2γ is specifically present in a subpopulation of transient amplifying progenitors, where it acts as a crucial promoter of proliferation and differentiation of adult-born glutamatergic granule neurons. Strikingly, deficiency of AP2γ in the adult brain compromises the generation of new glutamatergic neurons, with impact on the function of cortico-limbic circuits. Here, we share our view on how AP2γ integrates the transcriptional orchestration of glutamatergic neurogenesis in the adult hippocampus, and consequently, how it emerges as a novel molecular candidate to study the translation of environmental pressures into alterations of brain neuroplasticity in homeostatic, but also in neuropathological contexts.Bial Foundation (427/14); Northern Portugal Regional Operational Programme (NORTE 2020); European Regional Development Fund (FEDER) (projects NORTE-01-0145-FEDER-000013 e NORTE-01-0145-FEDER-000023); Competitiveness Factors Operational Programme (COMPETE)info:eu-repo/semantics/publishedVersio

Are uranium-contaminated soil and irrigation water a risk for human vegetable consumers? A study case with Solanum tuberosum L., Phaseolus vulgaris L. and Lactuca sativa L.

The knowledge of uranium concentration, in the products entering the human diet is of extreme importance because of their chemical hazard to health. Controlled field experiments with potatoes, beans and lettuce (Solanum tuberosum L., Phaseolus vulgaris L. and Lactuca sativa L.) were carried out in a contaminated soil used by local farmers located near a closed Portuguese uranium mine (Cunha Baixa, Mangualde). The soil with high average uranium levels (64–252 mg/kg) was divided in two plots, and irrigated with non-contaminated and uranium-contaminated water (\20 and [900 lg/L). Uranium maximum average concentration in the edible vegetables parts (mg/kg fresh weight) ranged in the following order: lettuce (234 lg/kg)[green bean (30 lg/kg)[potatoes without peel (4 lg/kg). Although uranium in soil, irrigation water and vegetables was high, the assessment of the health risk based on hazard quotient indicates that consumption of these vegetables does not represent potential adverse (no carcinogenic) effects for a local inhabitant during lifetime

Graphene-black phosphorus printed photodetectors

Layered materials (LMs) produced by liquid phase exfoliation (LPE) can be used as building blocks for optoelectronic applications. However, when compared with mechanically exfoliated flakes, or films prepared by chemical vapor deposition (CVD), LPE-based printed optoelectronic devices are limited by mobility, defects and trap states. Here, we present a scalable fabrication technique combining CVD with LPE LMs to overcome such limitations. We use black phosphorus inks, inkjet-printed on graphene on Si/SiO2, patterned by inkjet printing based lithography, and source and drain electrodes printed with an Ag ink, to prepare photodetectors (PDs). These have an external responsivity (R ext)∼337 A W−1 at 488 nm, and operate from visible (∼488 nm) to short-wave infrared (∼2.7 µm, R ext ∼ 48 mA W−1). We also use this approach to fabricate flexible PDs on polyester fabric, one of the most common used in textiles, achieving R ext ∼ 6 mA W−1 at 488 nm for an operating voltage of 1 V. Thus, our combination of scalable CVD and LPE techniques via inkjet printing is promising for wearable and flexible applications

Uso de fármacos psicoestimulantes en drogodependencias

El uso de medicamentos estimulantes es una cuestión de plena actualidad en psiquiatría, aunque su utilización y prescripción es controvertida . Fármacos como el metilfenidato, las anfetaminas, o el modafinilo están siendo utilizados y estudiados en distintas enfermedades psiquiátricas como el trastorno por déficit de atención e hiperactividad (TDAH), la dependencia de cocaína, en trastornos del sueño y en la depresión resistente. Todos estos fármacos tienen en común, igual que las drogas de abuso, que son medicamentos que actúan sobre el sistema dopaminérgico, que constituye la base neurobiológica del refuerzo fisiológico. Los estimulantes como el metilfenidato o el modafinilo son fármacos eficaces en el TDAH y han sido estudiados en el tratamiento de la dependencia de cocaína. En niños con TDAH el metilfenidato es un factor protector para el desarrollo de fármaco en la dependencia de cocaína, aunque son estudios preliminares, por lo que no se debe considerar que este totalmente demostrado que los fármacos psicoestimulantes sean eficaces en el tratamiento de esta dependencia. Aunque no son conocidos todos los mecanismos fisiopatológicos, parece crítico que el refuerzo, y por lo tanto el riesgo de dependencia, aparece cuando se producen incrementos rápidos dopaminérgicos y que los efectos terapéuticos aparecen cuando son lentos y mantenidos. Las características de uso a dosis bajas administradas por vía oral disminuyen el riesgo de abuso. Para realizar una adecuada prescripción es necesario aclarar, definitivamente, los mecanismos neuroquímicos en los que intervienen, y sus indicaciones en drogodependenciasStimulant drugs prescription is a controversial and current topic in psychiatry. Drugs such as methylphenidate, amphetamine compounds and modafinil have been trialed and used in attention deficit hyperactivity disorder (ADHD), sleep conditions, cocaine dependence and as an adjunct to antidepressants for depression. All these drugs, like stimulant drugs abuse, increase extracellular dopamine in the brain.This effect is associated with reinforcing as well as therapeutic effects. Methylphenidate and modafinil treatment of ADHD are associated with a reduced risk for later substance abuse among ADHD patients. There is evidence of the beneficial effects of the use of modafinil in cocaine dependence, altough there isn't conclusive evidence for the stimulants' efficacy in treatment of the stimulants' dependence. At this time, the physiopathology of drug abuse and dependence is unknown, but it's known that the very critical point is that the reinforcing effects are associated with rapid changes in dopamine increases, whereas the therapeutic effects are associated with slowly and smoothly rising dopamine levels, such as are achieved with low doses and oral administration. Due to this, it's necessary to study the neurobiological bases on which stimulants drugs are related, and their clinical use in dependence treatment

The CACCC-binding protein KLF3/BKLF represses a subset of KLF1/EKLF target genes and is required for proper erythroid maturation in vivo

The CACCC-box binding protein erythroid Kruppel-like factor (EKLF/KLF1) is a master regulator that directs the expression of many important erythroid genes. We have previously shown that EKLF drives transcription of the gene for a second KLF, basic Kruppel-like factor, or KLF3. We have now tested the in vivo role of KLF3 in erythroid cells by examining Klf3 knockout mice. KLF3-deficient adults exhibit a mild compensated anemia, including enlarged spleens, increased red pulp, and a higher percentage of erythroid progenitors, together with elevated reticulocytes and abnormal erythrocytes in the peripheral blood. Impaired erythroid maturation is also observed in the fetal liver. We have found that KLF3 levels rise as erythroid cells mature to become TER119(+). Consistent with this, microarray analysis of both TER119(-) and TER119(+) erythroid populations revealed that KLF3 is most critical at the later stages of erythroid maturation and is indeed primarily a transcriptional repressor. Notably, many of the genes repressed by KLF3 are also known to be activated by EKLF. However, the majority of these are not currently recognized as erythroid-cell-specific genes. These results reveal the molecular and physiological function of KLF3, defining it as a feedback repressor that counters the activity of EKLF at selected target genes to achieve normal erythropoiesis

Enhanced piezoelectric effect at the edges of stepped molybdenum disulfide nanosheets

The development of piezoelectric layered materials may be one of the key elements enabling expansion of nanotechnology, as they offer a solution for the construction of efficient transducers for a wide range of applications, including self-powered devices. Here, we investigate the piezoelectric effect in multilayer (ML) stepped MoS2 flakes obtained by liquid-phase exfoliation, which is especially interesting because it may allow the scalable fabrication of electronic devices using large area deposition techniques (e.g. solution casting, spray coating, inkjet printing). By using a conductive atomic force microscope we map the piezoelectricity of the MoS2 flakes at the nanoscale. Our experiments demonstrate the presence of electrical current densities above 100 A cm−2 when the flakes are strained in the absence of bias, and the current increases proportional to the bias. Simultaneously collected topographic and current maps demonstrate that the edges of stepped ML MoS2 flakes promote the piezoelectric effect, where the largest currents are observed. Density functional theory calculations are consistent with the ring-like piezoelectric potential generated when the flakes are strained, as well as the enhanced piezoelectric effect at edges. Our results pave the way to the design of piezoelectric devices using layered materials.We acknowledge funding from the Young 1000 Global Talent Recruitment Program of the Ministry of Education of China (KG and ML), the National Natural Science Foundation of China (grants no. 61502326, 41550110223, 11661131002, 11375127), the Jiangsu Government (grant no. BK20150343, BK20130280), the Ministry of Finance of China (grant no. SX21400213), the Young 973 National Program of the Chinese Ministry of Science and Technology (grant no. 2015CB932700) and the ERC Grant Hetero2D, the EU Graphene Flagship, EPSRC Grants EP/K01711X/1, EP/K017144/1, EP/L016087/1, EP/N010345/1, the Collaborative Innovation Center of Suzhou Nano Science & Technology, the Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices and the Priority Academic Program Development of Jiangsu Higher Education Institutions

Cytokine responses to two common respiratory pathogens in children are dependent on interleukin-1beta

Protracted bacterial bronchitis (PBB) in young children is a common cause of prolonged wet cough and may be a precursor to bronchiectasis in some children. Although PBB and bronchiectasis are both characterised by neutrophilic airway inflammation and a prominent interleukin (IL)-1β signature, the contribution of the IL-1β pathway to host defence is not clear. This study aimed to compare systemic immune responses against common pathogens in children with PBB, bronchiectasis and control children and to determine the importance of the IL-1β pathway. Non-typeable Haemophilus influenzae (NTHi) stimulation of peripheral blood mononuclear cells (PBMCs) from control subjects (n=20), those with recurrent PBB (n=20) and bronchiectasis (n=20) induced high concentrations of IL-1β, IL-6, interferon (IFN)-γ and IL-10. Blocking with an IL-1 receptor antagonist (IL-1Ra) modified the cellular response to pathogens, inhibiting cytokine synthesis by NTHi-stimulated PBMCs and rhinovirus-stimulated PBMCs (in a separate PBB cohort). Inhibition of IFN-γ production by IL-1Ra was observed across multiple cell types, including CD3+ T cells and CD56+ NK cells. Our findings highlight the extent to which IL-1β regulates the cellular immune response against two common respiratory pathogens. While blocking the IL-1β pathway has the potential to reduce inflammation, this may come at the cost of protective immunity against NTHi and rhinovirus.Alice C-H. Chen, Yang Xi, Melanie Carroll, Helen L. Petsky, Samantha J. Gardiner, Susan J. Pizzutto, Stephanie T. Yerkovich, Katherine J. Baines, Peter G. Gibson, Sandra Hodge, Ian B. Masters, Helen M. Buntain, Anne B. Chang and John W. Upha

Dietary patterns and risk of breast cancer

Background: Evidence is emerging that prudent/healthy dietary patterns might be associated with a reduced risk of breast cancer. Methods: Using data from the prospective Melbourne Collaborative Cohort Study, we applied principal factor analysis to 124 foods and beverages to identify dietary patterns and estimated their association with breast cancer risk overall and by tumour characteristics using Cox regression. Results: During an average of 14.1 years of follow-up of 20 967 women participants, 815 invasive breast cancers were diagnosed. Among the four dietary factors that we identified, only that characterised by high consumption of fruit and salad was associated with a reduced risk, with stronger associations observed for tumours not expressing oestrogen (ER) and progesterone receptors (PR). Compared with women in the lowest quintile of the factor score, the hazard ratio for women in the highest quintile was 0.92 (95% confidence interval (CI)=0.70-1.21; test for trend, P=0.5) for ER-positive or PR-positive tumours and 0.48 (95% CI=0.26-0.86; test for trend, P=0.002) for ER-negative and PR-negative tumours (test for homogeneity, P=0.01). Conclusion: Our study provides additional support for the hypothesis that a dietary pattern rich in fruit and salad might protect against invasive breast cancer and that the effect might be stronger for ER- and PR-negative tumours. © 2011 Cancer Research UK All rights reserved