Travelling to school by car diminishes opportunities for physical activity and contributes to traffic congestion and associated noise and air pollution. This meta-analysis examined sociodemographic characteristics and built environment associates of travelling to school by car compared to using active transport among New Zealand (NZ) adolescents. Four NZ studies (2163 adolescents) provided data on participants’ mode of travel to school, individual and school sociodemographic characteristics, distance to school and home-neighbourhood built-environment features. A one-step meta-analysis using individual participant data was performed in SAS. A final multivariable model was developed using stepwise logistic regression. Overall, 60.6% of participants travelled to school by car. When compared with active transport, travelling to school by car was positively associated with distance to school. Participants residing in neighbourhoods with high intersection density and attending medium deprivation schools were less likely to travel to school by car compared with their counterparts. Distance to school, school level deprivation and low home neighbourhood intersection density are associated with higher likelihood of car travel to school compared with active transport among NZ adolescents. Comprehensive interventions focusing on both social and built environment factors are needed to reduce car travel to school.Despite being one of the first-line treatments for osteoporosis, the bisphosphonate drug class exhibits an extremely low oral bioavailability ( less then 1%) due to poor absorption from the gastrointestinal tract. To overcome this, and to explore the potential for sustained drug release, bioerodible poly(lactic acid) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) implants loaded with the bisphosphonate alendronate sodium (ALN) were prepared via hot-melt extrusion. The rate of drug release in vitro was modulated by tailoring the ratio of lactide to glycolide in the polymer and by altering the ALN-loading of the implants. All investigated implants exhibited sustained ALN release in vitro between 25 to 130 days, where implants of greater glycolide composition and higher ALN-loadings released ALN more rapidly. All PLGA implants demonstrated a sigmoidal release profile, characterised by an initial surface dissolution phase, followed by a period of zero-order drug diffusion, then relaxation or erosion of the polymer chains that caused accelerated release over the subsequent days. Contrastingly, the PLA implants demonstrated a logarithmic release profile, characterised by a gradual decrease in ALN release over time.Perennial shrub-annual plant interactions play key roles in desert regions influencing the structure and dynamics of plant communities there. In the present study, carried out in northwestern Saudi Arabia, we examined the effect of Haloxylon salicornicum shrubs on their associated understory annual species across four consecutive growing seasons, along with a record of the seasonal rainfall patterns. We measured density and species richness of all the annual species in permanent quadrats located beneath individual shrubs, as well as in the spaces between shrubs. During wet growing season H. salicornicum shrubs significantly enhanced the density and species richness of sub-canopy species, whereas in the relatively dry seasons they exerted negative effects on the associated species. In all growing seasons, the presence of shrubs was associated with enhanced soil properties, including increased organic carbon content, silt + clay, and levels of nutrients (N, P and K). Shrubs improved soil moisture content beneath their canopies in the wet growing season, while in the dry seasons they had negative effects on water availability. Differences in effects of H. salicornicum on understory plants between growing seasons seem due to the temporal changes in the impact of shrubs on water availability. Our results suggest the facilitative effects of shrubs on sub-canopy annuals in arid ecosystems may switch to negative effects with increasing drought stress. We discuss the study in light of recent refinements of the well-known „stress-gradient hypothesis”.Keratinocytes undergo a complex differentiation process, coupled with extensive changes in gene expression through which they acquire distinctive features indispensable for cells that form the external body barrier-epidermis. Disturbed epidermal differentiation gives rise to multiple skin diseases. The involvement of epigenetic factors, such as DNA methylation or histone modifications, in the regulation of epidermal gene expression and differentiation has not been fully recognized yet. In this work we performed a CRISPR/Cas9-mediated knockout of SUV39H1, a gene-encoding H3K9 histone methyltransferase, in HaCaT cells that originate from spontaneously immortalized human keratinocytes and examined changes in the expression of selected differentiation-specific genes located in the epidermal differentiation complex (EDC) and other genomic locations by RT-qPCR. The studied genes revealed a diverse differentiation state-dependent or -independent response to a lower level of H3K9 methylation. We also show, by means of chromatin immunoprecipitation, that the expression of genes in the LCE1 subcluster of EDC was regulated by the extent of trimethylation of lysine 9 in histone H3 bound to their promoters. Changes in gene expression were accompanied by changes in HaCaT cell morphology and adhesion.The International Agency for Research on Cancer (IARC) at the World Health Organization (WHO) categorized in 2011 radiofrequency (RF) as a possible human carcinogen, Group 2B. During use of the handheld wireless phone, especially the smartphone, the thyroid gland is a target organ. During the 21st century, the incidence of thyroid cancer is increasing in many countries. We used the Swedish Cancer Register to study trends from 1970 to 2017. During that time period, the incidence increased statistically significantly in women with average annual percentage change (AAPC) +2.13%, 95% confidence interval (CI) +1.43, +2.83%. The increase was especially pronounced during 2010-2017 with annual percentage change (APC) +9.65%, 95% CI +6.68, +12.71%. In men, AAPC increased during 1970-2017 with +1.49%, 95% CI +0.71, +2.28%. Highest increase was found for the time period 2001-2017 with APC +5.26%, 95% CI +4.05, +6.49%. Similar results were found for all Nordic countries based on NORDCAN 1970-2016 with APC +5.83%, 95% CI +4.56, +7.12 in women from 2006 to 2016 and APC + 5.48%, 95% CI +3.92, +7.06% in men from 2005 to 2016. According to the Swedish Cancer Register, the increasing incidence was similar for tumors ≤4 cm as for tumors >4 cm, indicating that the increase cannot be explained by overdiagnosis. These results are in agreement with recent results on increased thyroid cancer risk associated with the use of mobile phones. We postulate that RF radiation is a causative factor for the increasing thyroid cancer incidence.This paper presents an instrument based on an equal-arm Michelson interferometer and a frequency-stabilized helium-neon laser. It is designed to record hydrosphere pressure variations in the frequency range from 0 (conventionally) to 1000 Hz, with accuracy of 0.24 mPa at sea depths of up to 50 m. The operating range of the instrument can be increased by order of magnitude by improving the registration system speed, and accuracy can be enhanced by using larger diameter membranes and/or their smaller thickness. The paper demonstrates some experimental results obtained on the supersensitive detector of hydrosphere pressure variations, confirming its high performance in the infrasonic and sonic ranges.Although the inhibitors of singly mutated epidermal growth factor receptor (EGFR) kinase are effective for the treatment of non-small cell lung cancer (NSCLC), their clinical efficacy has been limited due to the emergence of various double and triple EGFR mutants with drug resistance. It has thus become urgent to identify potent and selective inhibitors of triple mutant EGFRs resistant to first-, second-, and third-generation EGFR inhibitors. Herein, we report the discovery of potent and highly selective inhibitors of EGFR exon 19 p.E746_A750del/EGFR exon 20 p.T790M/EGFR exon 20 p.C797S (d746-750/T790M/C797S) mutant, which were derived via two-track virtual screening and de novo design. This two-track approach was performed so as to maximize and minimize the inhibitory activity against the triple mutant and the wild type, respectively. Extensive chemical modifications of the initial hit compounds led to the identification of several low-nanomolar inhibitors of the d746-750/T790M/C797S mutant. Among them, two compounds exhibited more than 104-fold selectivity in the inhibition of EGFRd746-750/T790M/C797S over the wild type. The formations of a hydrogen bond with the mutated residue Ser797 and the van der Waals contact with the mutated residue Met790 were found to be a common feature in the interactions between EGFRd746-750/T790M/C797S and the fourth-generation inhibitors. Such an exceptionally high selectivity could also be attributed to the formation of the hydrophobic contact with a Gly loop residue or the hydrogen bond with Asp855 in the activation loop. The discovery of the potent and selective EGFRd746-750/T790M/C797S inhibitors were actually made possible by virtue of the modified protein-ligand binding free energy function involving a new hydration free energy term with enhanced accuracy. The fourth-generation EGFR inhibitors found in this work are anticipated to serve as a new starting point for the discovery of anti-NSCLC medicines to overcome the problematic drug resistance.People with Alzheimer’s disease (AD) have significantly higher rates of subclinical and overt epileptiform activity. In animal models, oligomeric Aβ amyloid is able to induce neuronal hyperexcitability even in the early phases of the disease. Such aberrant activity subsequently leads to downstream accumulation of toxic proteins, and ultimately to further neurodegeneration and neuronal silencing mediated by concomitant tau accumulation. Several neurotransmitters participate in the initial hyperexcitable state, with increased synaptic glutamatergic tone and decreased GABAergic inhibition. These changes appear to activate excitotoxic pathways and, ultimately, cause reduced long-term potentiation, increased long-term depression, and increased GABAergic inhibitory remodelling at the network level. Brain hyperexcitability has therefore been identified as a potential target for therapeutic interventions aimed at enhancing cognition, and, possibly, disease modification in the longer term. Clinical trials are ongoing to evaluate the potential efficacy in targeting hyperexcitability in AD, with levetiracetam showing some encouraging effects. Newer compounds and techniques, such as gene editing via viral vectors or brain stimulation, also show promise. Diagnostic challenges include identifying best biomarkers for measuring sub-clinical epileptiform discharges. Determining the timing of any intervention is critical and future trials will need to carefully stratify participants with respect to the phase of disease pathology.