First-language grammar in the classroom : from consciousness raising to learner autonomy

According to students grammar lessons are boring and tedious. If you ask them why they will tell you that almost all they do in grammar lessons is to study and to practice 'rules' (see Micallef 1995). When asked how they feel about learning 'grammar', Form 3 students at a Juniour Lyceum stated that grammar " ... tad-dwejjaq, fiha qabda regoli, u li fiha ma nifhmu xejn. Kollox trid tistudja bl-amment ghall-eiami" (it is tedious, full of rules that we do not understand. Everything has to be studied for the exam). When asked why they think they should learn grammar they replied that without it "ma niktbux Malti tajjeb u importanti ghax tkun fl-eiamf' (we cannot write Maltese correctly, and it is important for the exam). Form 1 students were also asked to give their opinion about grammar and grammar lessons. They think that they need to study grammar "biex nispellu tajjelf' (to spell correctly); and that grammar is" dik li toqghod taghmel hafna jien, int, huwa, hija. Konna ndum u nimlew pages fil-Year 6 biex ghamilna tal-junior!" (full of conjugations. We used to fill pages of them when we were preparing to sit for the 11 + examination). Little do they know that as native speakers they make constant use of grammar in their everyday communication!peer-reviewe

An integrated coastal map for the Maltese Islands

The Maltese coastal area, comprising its associated resources and services, is of substantial importance to the Maltese economy. An innovative web interface has been developed to combine information from different sources, including coastal properties, physical features, resources and amenities, into an innovative comprehensive interactive map of the Maltese coastline. It serves as a general informative tool for users in the public domain, bringing different layers of data together, and targeting a delivery over smart media like mobile phones and tablets.peer-reviewe

Retigabine holds KV7 channels open and stabilizes the resting potential

The anticonvulsant Retigabine is a KV7 channel agonist used to treat hyperexcitability disorders in humans. Retigabine shifts the voltage dependence for activation of the heteromeric KV7.2/KV7.3 channel to more negative potentials, thus facilitating activation. Although the molecular mechanism underlying Retigabine\u27s action remains unknown, previous studies have identified the pore region of KV7 channels as the drug\u27s target. This suggested that the Retigabine-induced shift in voltage dependence likely derives from the stabilization of the pore domain in an open (conducting) conformation. Testing this idea, we show that the heteromeric KV7.2/KV7.3 channel has at least two open states, which we named O1 and O2, with O2 being more stable. The O1 state was reached after short membrane depolarizations, whereas O2 was reached after prolonged depolarization or during steady state at the typical neuronal resting potentials. We also found that activation and deactivation seem to follow distinct pathways, suggesting that the KV7.2/KV7.3 channel activity displays hysteresis. As for the action of Retigabine, we discovered that this agonist discriminates between open states, preferentially acting on the O2 state and further stabilizing it. Based on these findings, we proposed a novel mechanism for the therapeutic effect of Retigabine whereby this drug reduces excitability by enhancing the resting potential open state stability of KV7.2/KV7.3 channels. To address this hypothesis, we used a model for action potential (AP) in Xenopus laevis oocytes and found that the resting membrane potential became more negative as a function of Retigabine concentration, whereas the threshold potential for AP firing remained unaltered

A human phospholipid phosphatase activated by a transmembrane control module

In voltage-sensitive phosphatases (VSPs), a transmembrane voltage sensor domain (VSD) controls an intracellular phosphoinositide phosphatase domain, thereby enabling immediate initiation of intracellular signals by membrane depolarization. The existence of such a mechanism in mammals has remained elusive, despite the presence of VSP-homologous proteins in mammalian cells, in particular in sperm precursor cells. Here we demonstrate activation of a human VSP (hVSP1/TPIP) by an intramolecular switch. By engineering a chimeric hVSP1 with enhanced plasma membrane targeting containing the VSD of a prototypic invertebrate VSP, we show that hVSP1 is a phosphoinositide-5-phosphatase whose predominant substrate is PI(4,5)P(2). In the chimera, enzymatic activity is controlled by membrane potential via hVSP1\u27s endogenous phosphoinositide binding motif. These findings suggest that the endogenous VSD of hVSP1 is a control module that initiates signaling through the phosphatase domain and indicate a role for VSP-mediated phosphoinositide signaling in mammals

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Retigabine holds KV7 channels open and stabilizes the resting potential

The anticonvulsant Retigabine is a KV7 channel agonist used to treat hyperexcitability disorders in humans. Retigabine shifts the voltage dependence for activation of the heteromeric KV7.2/KV7.3 channel to more negative potentials, thus facilitating activation. Although the molecular mechanism underlying Retigabine\u27s action remains unknown, previous studies have identified the pore region of KV7 channels as the drug\u27s target. This suggested that the Retigabine-induced shift in voltage dependence likely derives from the stabilization of the pore domain in an open (conducting) conformation. Testing this idea, we show that the heteromeric KV7.2/KV7.3 channel has at least two open states, which we named O1 and O2, with O2 being more stable. The O1 state was reached after short membrane depolarizations, whereas O2 was reached after prolonged depolarization or during steady state at the typical neuronal resting potentials. We also found that activation and deactivation seem to follow distinct pathways, suggesting that the KV7.2/KV7.3 channel activity displays hysteresis. As for the action of Retigabine, we discovered that this agonist discriminates between open states, preferentially acting on the O2 state and further stabilizing it. Based on these findings, we proposed a novel mechanism for the therapeutic effect of Retigabine whereby this drug reduces excitability by enhancing the resting potential open state stability of KV7.2/KV7.3 channels. To address this hypothesis, we used a model for action potential (AP) in Xenopus laevis oocytes and found that the resting membrane potential became more negative as a function of Retigabine concentration, whereas the threshold potential for AP firing remained unaltered

UK smoke-free legislation: Changes in PM 2.5 concentrations in bars in Scotland, England, and Wales

Objective: Evaluate the effect of smoke-free legislation on fine particulate [particulate matter < 2.5 μm in diameter (PM2.5)] air pollution levels in bars in Scotland, England, and Wales. Design: Air quality was measured in 106 randomly selected bars in Scotland, England, and Wales before and after the introduction of smoking restrictions. Methods: PM2.5 concentrations were measured covertly for 30-min periods before smoke-free legislation was introduced, again at 1–2 months post-ban (except Wales) and then at 12-months post-baseline (except Scotland). In Scotland and England, overt measurements were carried out to assess bar workers’ full-shift personal exposures to PM2.5. Postcode data were used to determine socio-economic status of the bar location. Results: PM2.5 levels prior to smoke-free legislation were highest in Scotland (median 197 μg m−3), followed by Wales (median 184 μg m−3) and England (median 92 μg m−3). All three countries experienced a substantial reduction in PM2.5 concentrations following the introduction of the legislation with the median reduction ranging from 84 to 93%. Personal exposure reductions were also within this range. There was evidence that bars located in more deprived postcodes had higher PM2.5 levels prior to the legislation. Conclusions: Prior to legislation PM2.5 concentrations within bars across the UK were much higher than the 65 μg m−3 ‘unhealthy’ threshold for outdoor air quality as set by the US Environmental Protection Agency. Concentrations in Scottish and Welsh bars were, on average, two or more times greater than in English bars for which seasonal influences may be responsible. Legislation in all three countries produced improvements in indoor air quality that are consistent with other international studies