Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators

This Letter was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Scottish Universities Life Sciences Alliance (SULSA) in 2011Peer reviewedPostprin

Development of Liposomal Gemcitabine with High Drug Loading Capacity

Liposomes are widely used for systemic delivery of chemotherapeutic agents to reduce their nonspecific side effects. Gemcitabine (Gem) makes a great candidate for liposomal encapsulation due to the short half-life and nonspecific side effects; however, it has been difficult to achieve liposomal Gem with high drug loading capacity. Remote loading, which uses a transmembrane pH gradient to induce an influx of drug and locks the drug in the core as a sulfate complex, does not serve Gem as efficiently as doxorubicin (Dox) due to the low pKa value of Gem. Existing studies have attempted to improve Gem loading capacity in liposomes by employing lipophilic Gem derivatives or creating a high-concentration gradient for active loading into the hydrophilic cores (small volume loading). In this study, we combine the remote loading approach and small volume loading or hypertonic loading, a new approach to induce the influx of Gem into the preformed liposomes by high osmotic pressure, to achieve a Gem loading capacity of 9.4–10.3 wt % in contrast to 0.14–3.8 wt % of the conventional methods. Liposomal Gem showed a good stability during storage, sustained-release over 120 h in vitro, enhanced cellular uptake, and improved cytotoxicity as compared to free Gem. Liposomal Gem showed a synergistic effect with liposomal Dox on Huh7 hepatocellular carcinoma cells. A mixture of liposomal Gem and liposomal Dox delivered both drugs to the tumor more efficiently than a free drug mixture and showed a relatively good anti-tumor effect in a xenograft model of hepatocellular carcinoma. This study shows that bioactive liposomal Gem with high drug loading capacity can be produced by remote loading combined with additional approaches to increase drug influx into the liposomes

Shape programming lines of concentrated Gaussian curvature

Liquid crystal elastomers (LCEs) can undergo large reversible contractions along their nematic director upon heating or illumination. A spatially patterned director within a flat LCE sheet thus encodes a pattern of contraction on heating, which can morph the sheet into a curved shell, akin to how a pattern of growth sculpts a developing organism. Here we consider, theoretically, numerically and experimentally, patterns constructed from regions of radial and circular director, which, in isolation, would form cones and anticones. The resultant surfaces contain curved ridges with sharp V-shaped cross-sections, associated with the boundaries between regions in the patterns. Such ridges may be created in positively and negatively curved variants and, since they bear Gauss curvature (quantified here via the Gauss-Bonnet theorem), they cannot be flattened without energetically prohibitive stretch. Our experiments and numerics highlight that, although such ridges cannot be flattened isometrically, they can deform isometrically by trading the (singular) curvature of the V angle against the (finite) curvature of the ridge line. Furthermore, in finite thickness sheets, the sharp ridges are inevitably non-isometrically blunted to relieve bend, resulting in a modest smearing out of the encoded singular Gauss curvature. We close by discussing the use of such features as actuating linear features, such as probes, tongues and limbs, and highlighting the similarities between these patterns of shape change and those found during the morphogenesis of several biological systems.F.F. and M.W. were supported by the EPSRC [grant number EP/P034616/1]. M.W. is grateful for support from the ELBE Visiting Faculty Program, Dresden. D.D. was supported by the EPSRC Centre for Doctoral Training in Computational Methods for Materials Science [grant no. EP/L015552/1]. J.S.B. was supported by a UKRI “future leaders fellowship” [grant number MR/S017186/1]. This material is partially based upon work supported by the National Science Foundation under Grant DMR 2041671

Surgical training rotation design: effects of hospital type, rotation theme and duration

Background Entrants into UK surgical specialty training undertake a 2‐year programme of core surgical training, rotating through specialties for varying lengths of time, at different hospitals, to gain breadth of experience. This study aimed to assess whether these variables influenced core surgical trainee (CST) work productivity. Methods Intercollegiate Surgical Curriculum Programme portfolios of consecutive CSTs between 2016 and 2019 were examined. Primary outcome measures were workplace‐based assessment (WBA) completion, operative experience and academic outputs (presentations to learned societies, publications and audits). Results A total of 344 rotations by 111 CSTs were included. Incremental increases in attainment were observed related to the duration of core surgical training rotation. The median number of consultant‐validated WBAs completed during core surgical training were 48 (range 0–189), 54 (10–120) and 75 (6–94) during rotations consisting of 4‐, 6‐ and 12‐month posts respectively (P  < 0·001). Corresponding median operative caseloads (as primary surgeon) were 84 (range 3–357), 110 (44–394) and 134 (56–366) (P  < 0·001) and presentations to learned societies 0 (0–12), 0 (0–14) and 1 (0–5) (P = 0·012) respectively. Hospital type and specialty training theme were unrelated to workplace productivity. Multivariable analysis identified length of hospital rotation as the only factor independently associated with total WBA count (P = 0·001), completion of audit (P = 0·015) and delivery of presentation (P = 0·001) targets. Conclusion Longer rotations with a single educational supervisor, in one training centre, are associated with better workplace productivity. Consideration should be given to this when reconfiguring training programmes within the arena of workforce planning

Developmental expression of non-coding RNAs in Chlamydia trachomatis during normal and persistent growth

Chlamydia trachomatis is an obligate intracellular bacterium that exhibits a unique biphasic developmental cycle that can be disrupted by growth in the presence of IFN-γ and β-lactams, giving rise to an abnormal growth state termed persistence. Here we have examined the expression of a family of non-coding RNAs (ncRNAs) that are differentially expressed during the developmental cycle and the induction of persistence and reactivation. ncRNAs were initially identified using an intergenic tiling microarray and were confirmed by northern blotting. ncRNAs were mapped, characterized and compared with the previously described chlamydial ncRNAs. The 5′- and 3′-ends of the ncRNAs were determined using an RNA circularization procedure. Promoter predictions indicated that all ncRNAs were expressed from σ66 promoters and eight ncRNAs contained non-templated 3′-poly-A or poly-AG additions. Expression of ncRNAs was studied by northern blotting during (i) the normal developmental cycle, (ii) IFN-γ-induced persistence and (iii) carbenicillin-induced persistence. Differential temporal expression during the developmental cycle was seen for all ncRNAs and distinct differences in expression were seen during IFN-γ and carbenicillin-induced persistence and reactivation. A heterologous co-expression system was used to demonstrate that one of the identified ncRNAs regulated the expression of FtsI by inducing degradation of ftsI mRNA

Proof of surgical publication prowess: prospective observational study of factors associated with surrogate markers of academic reach

Background In the UK, general surgery higher surgical trainees (HSTs) must publish at least three peer-reviewed scientific articles (as first, second or corresponding author) to qualify for certification of completion of training (CCT). This study aimed to identify the factors associated with success in this arena. Methods Deanery rosters supplemented with data from the Intercollegiate Surgical Curriculum Programme, PubMed and ResearchGate were used to identify the profiles of consecutive HSTs. Primary outcomes were publication numbers at defined points in higher training (speciality training year (ST) 3–8); secondary outcomes were the Hirsch index and ResearchGate scores. Results Fifty-nine consecutive HSTs (24 women, 35 men) were studied. The median publication number was 3 (range 0–30). At least three published articles were obtained by 30 HSTs (51 per cent), with 19 (38 per cent) of 50 HSTs achieving this by ST4 (of whom 15 (79 per cent) had undertaken out of programme for research (OOPR) time) and 24 (80 per cent) by ST6. Thirteen HSTs (22 per cent) (ST3, 6; ST4, 4; ST5, 2; ST8, 1) had yet to publish at the time of writing. OOPR was associated with achieving three publications (24 of 35 (69 per cent) versus 6 of 24 (25 per cent) with no formal research time; P = 0·001), higher overall number of publications (median 6 versus 1 respectively; P < 0·001), higher ResearchGate score (median 23·37 versus 5·27; P < 0·001) and higher Hirsch index (median 3 versus 1; P < 0·001). In multivariable analysis, training grade (odds ratio (OR) 1·89, 95 per cent c.i. 0·01 to 3·52; P = 0·045) and OOPR (OR 6·55, 2·04 to 21·04; P = 0·002) were associated with achieving three publications. Conclusion If CCT credentials are to include publication profiles, HST programmes should incorporate research training in workforce planning

Public knowledge and behaviours relating to antibiotic use in Gulf Cooperation Council countries: A systematic review

© 2018 The Authors The aim of this review was to assess public knowledge and behaviours in relation to antibiotic use in GCC countries. A systematic review was performed using MEDLINE, EMBASE and other relevant databases. Cross-sectional studies published from January 2000 to June 2017 relating to public knowledge and behaviours towards antibiotic use were included. Overall nine studies met the inclusion criteria for this systematic review. Nearly half of general public respondents in the GCC region reported a lack of knowledge about antibiotic use and showed negative attitudes towards antibiotic utilisation. Penicillin was the most frequently misused antibiotic, particularly for self-medication. Most respondents declared that they obtained information on antibiotics from pharmacists. Pharmacies were the major source of antibiotics used for self-medication. A multi-disciplinary approach must be put in place to educate the public on appropriate antibiotic use, to improve policies regarding the rational prescription of antimicrobials and to increase regulation enforcement

Glycosylation defects underlying fetal alcohol spectrum disorder: a novel pathogenetic model: “When the wine goes in, strange things come out” – S.T. Coleridge, The Piccolomini

Fetal alcohol spectrum disorder (FASD) is an umbrella term used to describe the craniofacial dysmorphic features, malformations, and disturbances in growth, neurodevelopment and behavior occurring in individuals prenatally exposed to alcohol. Fetal alcohol syndrome (FAS) represents the severe end of this spectrum. Many pathophysiological mechanisms have hitherto been proposed to account for the disrupted growth and morphogenesis seen in FAS. These include impaired cholesterol-modification of the Sonic hedgehog morphogen, retinoic acid deficiency, lipoperoxidative damage due to alcohol-induced reactive oxygen species combined with reduced antioxidant defences, and malfunctioning cell adhesion molecules. In this report, we propose a completely novel concept regarding the pathogenesis of FAS. Based on our observation that transferrin isoelectric focusing (TIEF) – the most widely used screening tool for congenital disorders of glycosylation (CDG) – was transiently abnormal in a newborn with FAS and a confirmed maternal history of gestational alcohol abuse, we came to believe that FAS exemplifies a congenital disorder of glycosylation secondary to alcohol-inflicted disruption of (N-linked) protein glycosylation. Various pieces of evidence were found in the literature to substantiate this hypothesis. This observation implies, among others, that one might need to consider the possibility of maternal alcohol consumption in newborns with transient glycosylation abnormalities. We also present an integrated pathophysiological model of FAS, which incorporates all existing theories mentioned above as well as our novel concept. This model highlights the pivotal role of disrupted isoprenoid metabolism in the origination of FAS

The Palestinian primary ciliary dyskinesia population: first results of the diagnostic, and genetic spectrum

BACKGROUND: Diagnostic testing for primary ciliary dyskinesia (PCD) started in 2013 in Palestine. We aimed to describe the diagnostic, genetic and clinical spectrum of the Palestinian PCD population. METHODS: Individuals with symptoms suggestive of PCD were opportunistically considered for diagnostic testing: nasal nitric oxide (nNO) measurement, transmission electron microscopy (TEM) and/or PCD genetic panel or whole-exome testing. Clinical characteristics of those with a positive diagnosis were collected close to testing including forced expiratory volume in 1 s (FEV1) Global Lung Index z-scores and body mass index z-scores. RESULTS: 68 individuals had a definite positive PCD diagnosis, 31 confirmed by genetic and TEM results, 23 by TEM results alone, and 14 by genetic variants alone. 45 individuals from 40 families had 17 clinically actionable variants and four had variants of unknown significance in 14 PCD genes. CCDC39, DNAH11 and DNAAF11 were the most commonly mutated genes. 100% of variants were homozygous. Patients had a median age of 10.0 years at diagnosis, were highly consanguineous (93%) and 100% were of Arabic descent. Clinical features included persistent wet cough (99%), neonatal respiratory distress (84%) and situs inversus (43%). Lung function at diagnosis was already impaired (FEV1 z-score median −1.90 (−5.0–1.32)) and growth was mostly within the normal range (z-score mean −0.36 (−3.03–2.57). 19% individuals had finger clubbing. CONCLUSIONS: Despite limited local resources in Palestine, detailed geno- and phenotyping forms the basis of one of the largest national PCD populations globally. There was notable familial homozygosity within the context of significant population heterogeneity

Characterization and intracellular localization of putative Chlamydia pneumoniae effector proteins

We here describe four proteins of Chlamydia pneumoniae, which might play a role in host-pathogen interaction. The hypothetical bacterial proteins CPn0708 and CPn0712 were detected in Chlamydia pneumoniae-infected host cells by indirect immunofluorescence tests with polyclonal antisera raised against the respective proteins. While CPn0708 was localized within the inclusion body, CPn0712 was identified in the inclusion membrane and in the surrounding host cell cytosol. CPn0712 colocalizes with actin, indicating its possible interaction with components of the cytoskeleton. Investigations on CPn0809 and CPn1020, two Chlamydia pneumoniae proteins previously described to be secreted into the host cell cytosol, revealed colocalization with calnexin, a marker for the ER. Neither CPn0712, CPn0809 nor CPn1020 were able to inhibit host cell apoptosis. Furthermore, transient expression of CPn0712, CPn0809 and CPn1020 by the host cell itself had no effect on subsequent infection with Chlamydia pneumoniae. However, microarray analysis of CPn0712-expressing host cells revealed six host cell genes which were regulated as in host cells infected with Chlamydia pneumoniae, indicating the principal usefulness of heterologous expression to study the effect of Chlamydia pneumoniae proteins on host cell modulation