Triggered release from lipid bilayer vesicles by an artificial transmembrane signal transduction system

The on-demand delivery of drug molecules from nano-scale carriers with spatio-temporal control is a key challenge in modern medicine. Here we show that lipid bilayer vesicles (liposomes) can be triggered to release an encapsulated molecular cargo in response to an external control signal by employing an artificial transmembrane signal transduction mechanism. A synthetic signal transducer embedded in the lipid bilayer membrane acts as a switchable catalyst, catalyzing the formation of surfactant molecules inside the vesicle in response to a change in external pH. The surfactant permeabilises the lipid bilayer membrane to facilitate release of an encapsulated hydrophilic cargo. In the absence of the pH control signal, the catalyst is inactive and the cargo remains encapsulated within the vesicle.Oppenheimer Research Fund for an Early Career Research Fellowshi

Ryanodine receptors are part of the myospryn complex in cardiac muscle

The Cardiomyopathy–associated gene 5 (Cmya5) encodes myospryn, a large tripartite motif (TRIM)-related protein found predominantly in cardiac and skeletal muscle. Cmya5 is an expression biomarker for a number of diseases affecting striated muscle and may also be a schizophrenia risk gene. To further understand the function of myospryn in striated muscle, we searched for additional myospryn paralogs. Here we identify a novel muscle-expressed TRIM-related protein minispryn, encoded by Fsd2, that has extensive sequence similarity with the C-terminus of myospryn. Cmya5 and Fsd2 appear to have originated by a chromosomal duplication and are found within evolutionarily-conserved gene clusters on different chromosomes. Using immunoaffinity purification and mass spectrometry we show that minispryn co-purifies with myospryn and the major cardiac ryanodine receptor (RyR2) from heart. Accordingly, myospryn, minispryn and RyR2 co-localise at the junctional sarcoplasmic reticulum of isolated cardiomyocytes. Myospryn redistributes RyR2 into clusters when co-expressed in heterologous cells whereas minispryn lacks this activity. Together these data suggest a novel role for the myospryn complex in the assembly of ryanodine receptor clusters in striated muscle

Intraperitoneal drain placement and outcomes after elective colorectal surgery: international matched, prospective, cohort study

Despite current guidelines, intraperitoneal drain placement after elective colorectal surgery remains widespread. Drains were not associated with earlier detection of intraperitoneal collections, but were associated with prolonged hospital stay and increased risk of surgical-site infections.Background Many surgeons routinely place intraperitoneal drains after elective colorectal surgery. However, enhanced recovery after surgery guidelines recommend against their routine use owing to a lack of clear clinical benefit. This study aimed to describe international variation in intraperitoneal drain placement and the safety of this practice. Methods COMPASS (COMPlicAted intra-abdominal collectionS after colorectal Surgery) was a prospective, international, cohort study which enrolled consecutive adults undergoing elective colorectal surgery (February to March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis of postoperative intraperitoneal collections; rate of surgical site infections (SSIs); time to discharge; and 30-day major postoperative complications (Clavien-Dindo grade at least III). After propensity score matching, multivariable logistic regression and Cox proportional hazards regression were used to estimate the independent association of the secondary outcomes with drain placement. Results Overall, 1805 patients from 22 countries were included (798 women, 44.2 per cent; median age 67.0 years). The drain insertion rate was 51.9 per cent (937 patients). After matching, drains were not associated with reduced rates (odds ratio (OR) 1.33, 95 per cent c.i. 0.79 to 2.23; P = 0.287) or earlier detection (hazard ratio (HR) 0.87, 0.33 to 2.31; P = 0.780) of collections. Although not associated with worse major postoperative complications (OR 1.09, 0.68 to 1.75; P = 0.709), drains were associated with delayed hospital discharge (HR 0.58, 0.52 to 0.66; P < 0.001) and an increased risk of SSIs (OR 2.47, 1.50 to 4.05; P < 0.001). Conclusion Intraperitoneal drain placement after elective colorectal surgery is not associated with earlier detection of postoperative collections, but prolongs hospital stay and increases SSI risk

Molecular carbon allotropes: cyclo[n]carbons

This thesis details the first structural characterisation of a cyclo[n]carbon. Carbon allotropes built from rings of two-coordinate atoms, known as cyclo[n]carbons, have fascinated chemists for many years, but until now they could not be isolated or structurally characterised, due to their high reactivity. This thesis describes two different routes to cyclo[18]carbon by atomic manipulation of a cyclocarbon oxide C24O6 and a bromocyclocarbon C18Br6 precursor on bilayer NaCl on Cu(111) at 5 K. It then discusses initial attempts towards the on-surface synthesis of antiaromatic cyclo[n]carbons. Chapter 1 reviews the history of synthetic carbon allotropes, in particular the cyclo[n]carbons, including all theoretical and experimental investigations into these molecular carbon allotropes. An introduction to the field of scanning probe microscopy is then detailed. Chapter 2 discusses the on-surface generation of cyclo[18]carbon by elimination of carbon monoxide from a cyclocarbon oxide molecule, C24O6. Characterisation of cyclo[18]carbon by high-resolution atomic force microscopy reveals a polyynic structure with defined positions of alternating triple and single bonds. The high reactivity of cyclocarbon and the cyclocarbon oxides allows covalent coupling by atom manipulation, which has significant promise for the synthesis of other carbon allotropes and carbon-rich materials from the coalescence of cyclocarbon molecules. Chapter 3 details the synthesis of cyclo[18]carbon by dehalogenation of a bromocyclocarbon precursor, C18Br6, in 64% yield. This method generates cyclo[18]carbon in a higher yield than from the cyclocarbon oxide, C24O6. The experimental images of C18 are compared with simulated images for four theoretical model geometries, including possible bond-angle alternation: D18h cumulene, D9h polyyne, D9h cumulene and C9h polyyne. Cumulenic structures with (D9h) and without (D18h) bond-angle alternation can be excluded. Polyynic structures with (C9h) and without (D9h) bond-angle alternation both show a good agreement with the experiment and are challenging to differentiate. Chapter 4 explores the synthesis and properties of a series of cyclocarbon oxides as precursors to antiaromatic cyclo[n]carbons. The synthesis of cyclocarbon oxide precursors to cyclo[24]carbon (C32O8) and cyclo[20]carbon (C28O8) is discussed however the on-surface sublimation of both molecules proves unsuccessful. Initial investigations into the synthesis of a cyclo[16]carbon precursor, C22O6, are also detailed. Finally, a number of possible future avenues for this project are described.</p

A short history of cyclocarbons

The cyclocarbons constitute a family of molecular carbon allotropes consisting of rings of two-coordinate atoms. Their high reactivities make them difficult to study, but there has been much progress towards understanding their structures and properties. Here we provide a short account of theoretical and experimental work on these carbon rings, and highlight opportunities for future research in this field. The cyclocarbons constitute a family of molecular carbon allotropes consisting of rings of two-coordinate atoms. Their high reactivities make them difficult to study, but there has been much progress towards understanding their structures and properties. Here we provide a short account of theoretical and experimental work on these carbon rings, and highlight opportunities for future research in this field

An sp-hybridized molecular carbon allotrope, cyclo[18]carbon.

Carbon allotropes built from rings of two-coordinate atoms, known as cyclo[n]carbons, have fascinated chemists for many years, but until now they could not be isolated or structurally characterized, due to their high reactivity. We generated cyclo[18]carbon (C18) using atom manipulation on bilayer NaCl on Cu(111) at 5 Kelvin by eliminating carbon monoxide from a cyclocarbon oxide molecule C24O6 Characterization of cyclo[18]carbon by high-resolution atomic force microscopy revealed a polyynic structure with defined positions of alternating triple and single bonds. The high reactivity of cyclocarbon and cyclocarbon oxides allows covalent coupling between molecules to be induced by atom manipulation, opening an avenue for the synthesis of other carbon allotropes and carbon-rich materials from the coalescence of cyclocarbon molecules