Probing Binding Interactions of Cytisine Derivatives to the α4β2 Nicotinic Acetylcholine Receptor

Nicotinic acetylcholine receptors (nAChRs) are crucial for communication between synapses in the central nervous system. As such, they are also implicated in several neuropsychiatric and addictive diseases. Cytisine is a partial agonist of some nAChRs and has been used for smoking cessation. Previous studies have established a binding model for several agonists to several nAChR subtypes. Here, we evaluate the extent to which this model applies to cytisine at the α4β2 nAChR, which is a subtype that is known to play a prominent role in nicotine addiction. Along with the commonly seen cation−π interaction and two hydrogen bonds, we find that cytisine makes a second cation−π interaction at the agonist binding site. We also evaluated a series of C(10)-substituted cytisine derivatives, using two-electrode voltage-clamp electrophysiology and noncanonical amino acid mutagenesis. Double-mutant cycle analyses revealed that C(10) substitution generally strengthens the newly established second cation−π interaction, while it weakens the hydrogen bond typically seen to LeuE in the complementary subunit. The results suggest a model for how cytisine derivatives substituted at C(10) (as well as C(9)/C(10)) adjust their binding orientation, in response to pyridone ring substitution

The EQ-5D-3L administered by text message compared to the paper version for hard-to-reach populations in a rural South African trauma setting:a measurement equivalence study

INTRODUCTION: Administering patient-reported outcome measures (PROMs) by text message may improve response rate in hard-to-reach populations. This study explored cultural acceptability of PROMs and compared measurement equivalence of the EQ-5D-3L administered on paper and by text message in a rural South African setting. MATERIALS AND METHODS: Participants with upper or lower limb orthopaedic pathology were recruited. The EQ-5D was administered first on paper and then by text message after 24 h and 7 days. Differences in mean scores for paper and text message versions of the EQ-5D were evaluated. Test–retest reliability between text message versions was evaluated using Intraclass Correlation Coefficients (ICCs). RESULTS: 147 participants completed a paper EQ-5D. Response rates were 67% at 24 h and 58% at 7 days. There were no differences in means between paper and text message responses for the EQ-5D Index (p = 0.95) or EQ-5D VAS (p = 0.26). There was acceptable agreement between the paper and 24-h text message EQ-5D Index (0.84; 95% Confidence Interval (CI) 0.78–0.89) and EQ-5D VAS (0.73; 95% CI 0.64–0.82) and acceptable agreement between the 24-h and 7-day text message EQ-Index (0.72; CI 0.62–0.82) and EQ-VAS (0.72; CI 0.62–0.82). Non-responder traits were increasing age, Xhosa as first language and lower educational levels. CONCLUSIONS: Text messaging is equivalent to paper-based measurement of EQ-5D in this setting and is thus a viable tool for responders. Non-responders had similar socioeconomic characteristics and attrition rates to traditional modes of administration. The EQ-5D by text message offers potential clinical and research uses in hard-to-reach populations

Probing Binding Interactions of Cytisine Derivatives to the α4β2 Nicotinic Acetylcholine Receptor

Nicotinic acetylcholine receptors (nAChRs) are crucial for communication between synapses in the central nervous system. As such, they are also implicated in several neuropsychiatric and addictive diseases. Cytisine is a partial agonist of some nAChRs and has been used for smoking cessation. Previous studies have established a binding model for several agonists to several nAChR subtypes. Here, we evaluate the extent to which this model applies to cytisine at the α4β2 nAChR, which is a subtype that is known to play a prominent role in nicotine addiction. Along with the commonly seen cation−π interaction and two hydrogen bonds, we find that cytisine makes a second cation−π interaction at the agonist binding site. We also evaluated a series of C(10)-substituted cytisine derivatives, using two-electrode voltage-clamp electrophysiology and noncanonical amino acid mutagenesis. Double-mutant cycle analyses revealed that C(10) substitution generally strengthens the newly established second cation−π interaction, while it weakens the hydrogen bond typically seen to LeuE in the complementary subunit. The results suggest a model for how cytisine derivatives substituted at C(10) (as well as C(9)/C(10)) adjust their binding orientation, in response to pyridone ring substitution

Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (the SToP-BPD study): Statistical analysis plan

Background: Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth with short-term and long-term adverse consequences. Although the glucocorticoid dexamethasone has been proven to be beneficial for the prevention of BPD, there are concerns about an increased risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. The aim of the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (SToP-BPD) trial is to assess the efficacy and safety of postnatal hydrocortisone administration for the reduction of death or BPD in ventilator-dependent preterm infants. Methods/design: The SToP-BPD study is a multicentre, double-blind, placebo-controlled hydrocortisone trial in preterm infants at risk for BPD. After parental informed consent is obtained, ventilator-dependent infants are randomly allocated to hydrocortisone or placebo treatment during a 22-day period. The primary outcome measure is the composite outcome of death or BPD at 36 weeks postmenstrual age. Secondary outcomes are short-term effects on pulmonary condition and long-term neurodevelopmental sequelae assessed at 2 years corrected age. Complications of treatment, other serious adverse events and suspected unexpected serious adverse reactions are reported as safety outcomes. This pre-specified statistical analysis plan was written and submitted without knowledge of the unblinded data

The Early Royal Society and Visual Culture

Recent studies have fruitfully examined the intersection between early modern science and visual culture by elucidating the functions of images in shaping and disseminating scientific knowledge. Given its rich archival sources, it is possible to extend this line of research in the case of the Royal Society to an examination of attitudes towards images as artefacts –manufactured objects worth commissioning, collecting and studying. Drawing on existing scholarship and material from the Royal Society Archives, I discuss Fellows’ interests in prints, drawings, varnishes, colorants, images made out of unusual materials, and methods of identifying the painter from a painting. Knowledge of production processes of images was important to members of the Royal Society, not only as connoisseurs and collectors, but also as those interested in a Baconian mastery of material processes, including a “history of trades”. Their antiquarian interests led to discussion of painters’ styles, and they gradually developed a visual memorial to an institution through portraits and other visual records.AH/M001938/1 (AHRC

Diet in Peru's Pre-Hispanic Central Coast.

The Tablada de Lurín cemetery (200 BC – AD 200; Lima, Peru) is characterised by two mortuary phases. Based on associated grave finds and the lack of habitation sites near the cemetery, it has been hypothesised that both burial populations came from a certain distance of the site (ca. 20 km) and that they relied on land rather than marine resources. We tested these hypotheses, based on material culture, through stable isotope analysis. The aim was to understand the populations’ diet and geographic origins. We sampled 47 human individuals and eleven sets of faunal remains from both phases for stable isotope analysis (carbon, nitrogen, sulphur and oxygen) of bone and dental collagen, and apatite. Modern samples of autochthonous food were also tested as a baseline for comparison. The results showed preservation differences between the remains from both phases. Individuals from Phase 1 provided the best isotopic dataset and showed consumption of protein from marine resources and C4 plants. On the other hand, bioapatite carbon and oxygen stable isotope results from both phases highlighted differences in C4 plant consumption and individuals of possible non-local origin. The results underline the need to study further the effect of brewed or cooked beverages on bioapatite oxygen levels. Finally, results from Phase 1 fit with the broader dietary pattern evident in other Andean sites, where coastal populations consumed marine protein and C4 plants, as opposed to highland populations who relied on terrestrial protein sources and C3 plants

Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models.

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug-omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug-drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities. [Abstract copyright: © 2023. The Author(s).

Systemic hydrocortisone to prevent bronchopulmonary dysplasia in preterm infants (the SToP-BPD study); a multicenter randomized placebo controlled trial

<p>Abstract</p> <p>Background</p> <p>Randomized controlled trials have shown that treatment of chronically ventilated preterm infants after the first week of life with dexamethasone reduces the incidence of the combined outcome death or bronchopulmonary dysplasia (BPD). However, there are concerns that dexamethasone may increase the risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. So far no randomized controlled trial has investigated its efficacy when administered after the first week of life to ventilated preterm infants.</p> <p>Methods/Design</p> <p>The SToP-BPD trial is a randomized double blind placebo controlled multicenter study including 400 very low birth weight infants (gestational age < 30 weeks and/or birth weight < 1250 grams), who are ventilator dependent at a postnatal age of 7 - 14 days. Hydrocortisone (cumulative dose 72.5 mg/kg) or placebo is administered during a 22 day tapering schedule. Primary outcome measure is the combined outcome mortality or BPD at 36 weeks postmenstrual age. Secondary outcomes are short term effects on the pulmonary condition, adverse effects during hospitalization, and long-term neurodevelopmental sequelae assessed at 2 years corrected gestational age. Analysis will be on an intention to treat basis.</p> <p>Discussion</p> <p>This trial will determine the efficacy and safety of postnatal hydrocortisone administration at a moderately early postnatal onset compared to placebo for the reduction of the combined outcome mortality and BPD at 36 weeks postmenstrual age in ventilator dependent preterm infants.</p> <p>Trial registration number</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2768">NTR2768</a></p