Natural environments and suicide mortality in the Netherlands: a cross-sectional, ecological study

Background: Natural outdoor environments, such as green spaces (ie, grass, forests, or parks), blue spaces (ie, visible bodies of fresh or salt water), and coastal proximity, have been increasingly shown to promote mental health. However, little is known about how and the extent to which these natural environments are associated with suicide mortality. Our aim was to investigate whether the availability of green space and blue space within people's living environments and living next to the coast are protective against suicide mortality. Methods: In this cross-sectional, ecological study, we analysed officially confirmed deaths by suicide between 2005 and 2014 per municipality in the Netherlands. We calculated indexes to measure the proportion of green space and blue space per municipality and the coastal proximity of each municipality using a geographical information system. We fitted Bayesian hierarchical Poisson regressions to assess associations between suicide risk, green space, blue space, and coastal proximity, adjusted for risk and protective factors. Findings: Municipalities with a large proportion of green space (relative risk 0·879, 95% credibility interval 0·779–0·991) or a moderate proportion of green space (0·919, 0·846–0·998) showed a reduced suicide risk compared with municipalities with less green space. Green space did not differ according to urbanicity in relation to suicide. Neither blue space nor coastal proximity was associated with suicide risk. The geographical variation in the residual relative suicide risk was substantial and the south of the Netherlands was at high risk. Interpretation: Our findings support the notion that exposure to natural environments, particularly to greenery, might have a role in reducing suicide mortality. If confirmed by future studies on an individual level, the consideration of environmental exposures might enrich suicide prevention programmes

Moving towards the magnetoelectric graphene transistor

The interfacial charge transfer between mechanically exfoliated few-layer graphene and Cr2O3 (0001) surfaces has been investigated. Electrostatic force microscopy and Kelvin probe force microscopy studies point to hole doping of few-layer graphene, with up to a 150 meV shift in the Fermi level, an aspect that is confirmed by Raman spectroscopy. Density functional theory calculations furthermore confirm the p-type nature of the graphene/chromia interface and suggest that the chromia is able to induce a significant carrier spin polarization in the graphene layer. A large magnetoelectrically controlled magneto-resistance can therefore be anticipated in transistor structures based on this system, a finding important for developing graphene-based spintronic applications

A potent antagonist of protease-activated receptor 2 that inhibits multiple signaling functions in human cancer cells

Protease-activated receptor 2 (PAR2) is a cell surface protein linked to G-protein dependent and independent intracellular signaling pathways that produce a wide range of physiological responses, including those related to metabolism, inflammation, pain and cancer. Certain proteases, peptides and nonpeptides are known to potently activate PAR2. However, no effective potent PAR2 antagonists have been reported yet despite their anticipated therapeutic potential. This study investigates antagonism of key PAR2-dependent signaling properties and functions by an imidazopyridazine compound, I-191, in cancer cells. At nanomolar concentrations, I-191 inhibited PAR2 binding of, and activation by, structurally distinct PAR2 agonists (trypsin, peptide, nonpeptide) in a concentration-dependent manner in HT-29 cells. I-191 potently attenuated multiple PAR2-mediated intracellular signaling pathways leading to Ca2+ release, ERK1/2 phosphorylation, RhoA activation and inhibition of forskolin-induced cAMP accumulation. The mechanism of action of I-191 was investigated using binding and calcium mobilization studies in HT29 cells where I-191 was shown to be non-competitive and a negative allosteric modulator of the agonist 2f-LIGRL-NH2. The compound alone did not activate these PAR2-mediated pathways, even at high micromolar concentrations, indicating no bias in these signaling properties. I-191 also potently inhibited PAR2-mediated downstream functional responses, including expression and secretion of inflammatory cytokines, cell apoptosis and migration, in human colon (HT-29) and breast (MDA-MB-231) cancer cells. These findings indicate that I-191 is a potent PAR2 antagonist that inhibits multiple PAR2-induced signaling pathways and functional responses. I-191 may be a valuable tool for characterising PAR2 functions in cancer and in other cellular, physiological and disease settings

PAR2 modulators derived from GB88

PAR2 antagonists have potential for treating inflammatory, respiratory, gastrointestinal, neurological, and metabolic disorders, but few antagonists are known. Derivatives of GB88 (3) suggest that all four of its components bind at distinct PAR2 sites with the isoxazole, cyclohexylalanine, and isoleucine determining affinity and selectivity, while the C-terminal substituent determines agonist/antagonist function. Here we report structurally similar PAR2 ligands with opposing functions (agonist vs antagonist) upon binding to PAR2. A biased ligand AY117 (65) was found to antagonize calcium release induced by PAR2 agonists trypsin and hexapeptide 2f-LIGRLO-NH2 (IC50 2.2 and 0.7 mu M, HT29 cells), but it was a selective PAR2 agonist in inhibiting cAMP stimulation and activating ERK1/2 phosphorylation. It showed antiinflammatory properties both in vitro and in vivo

Anti-epileptic effect of Ganoderma lucidum polysaccharides by inhibition of intracellular calcium accumulation and stimulation of expression of CaMKII a in epileptic hippocampal neurons

Purpose: To investigate the mechanism of the anti-epileptic effect of Ganoderma lucidum polysaccharides (GLP), the changes of intracellular calcium and CaMK II a expression in a model of epileptic neurons were investigated. Method: Primary hippocampal neurons were divided into: 1) Control group, neurons were cultured with Neurobasal medium, for 3 hours; 2) Model group I: neurons were incubated with Mg2+ free medium for 3 hours; 3) Model group II: neurons were incubated with Mg2+ free medium for 3 hours then cultured with the normal medium for a further 3 hours; 4) GLP group I: neurons were incubated with Mg2+ free medium containing GLP (0.375 mg/ml) for 3 hours; 5) GLP group II: neurons were incubated with Mg2+ free medium for 3 hours then cultured with a normal culture medium containing GLP for a further 3 hours. The CaMK II a protein expression was assessed by Western-blot. Ca2+ turnover in neurons was assessed using Fluo-3/AM which was added into the replacement medium and Ca2+ turnover was observed under a laser scanning confocal microscope. Results: The CaMK II a expression in the model groups was less than in the control groups, however, in the GLP groups, it was higher than that observed in the model group. Ca2+ fluorescence intensity in GLP group I was significantly lower than that in model group I after 30 seconds, while in GLP group II, it was reduced significantly compared to model group II after 5 minutes. Conclusion: GLP may inhibit calcium overload and promote CaMK II a expression to protect epileptic neuron

Efficient chemical synthesis of human complement protein C3a

We report the total chemical synthesis of human C3a by one-pot native chemical ligation of three unprotected peptide segments, followed by efficient in vitro folding that yielded the anaphylatoxin C3a in high yield and excellent purity. Synthetic C3a was fully active and its crystal structure at 2.1 Å resolution showed 3 helices and a C-terminal turn motif

Temporal trends and patterns of infective endocarditis in a Chinese population:A territory-wide study in Hong Kong (2002-2019)

BACKGROUND: The characteristics of infective endocarditis (IE) in Asians are poorly understood. Therefore, we aim to describe the epidemiological trends and clinical features of IE in Hong Kong. METHODS: All patients with incident IE from 2002–2019 in a territory-wide clinical database in Hong Kong were identified. We studied the age- and sex-adjusted and one-year mortality of IE between 2002 and 2019 and identified significant contributors to 1-year all-cause death using the attributable fraction. We used propensity score and inverse propensity of treatment weighting to study the association of surgery with mortality. FINDINGS: A total of 5139 patients (60.4 ± 18.2years, 37% women) were included. The overall incidence of IE was 4.9 per 100,000 person-year, which did not change over time (P = 0.17). Patients in 2019 were older and more comorbid than those in 2002. The one-year crude mortality rate was 30% in 2002, which did not change significantly over time (P = 0.10). Between 2002 and 2019, the rate of surgery increased and was associated with a 51% risk reduction in 1-year all-cause mortality (Hazard Ratio 0.49 [0.28–0.87], P = 0.015). Advanced age (attributable fraction 19%) and comorbidities (attributable fraction 15%) were significant contributors to death. INTERPRETATION: The incidence of IE in Hong Kong did not change between 2002 and 2019. Patients with IE in 2019 were older and had more comorbidities than those in 2002. Mortality of IE remains persistently high in Hong Kong. Together, these data can guide public health strategies to improve the outcomes of patients with IE. FUNDING: This work was supported by Sanming Project of Medicine in Shenzhen, China [No. SZSM201911020] and HKU-SZH Fund for Shenzhen Key Medical Discipline [No. SZXK2020081]