Programmable monodisperse glyco-multivalency using self-assembled coordination cages as scaffolds

The multivalent presentation of glycans leads to enhanced binding avidity to lectins due to the cluster glycoside effect. Most materials used as scaffolds for multivalent glycan arrays, such as polymers or nanoparticles, have intrinsic dispersity: meaning that in any sample, a range of valencies are presented and it is not possible to determine which fraction(s) are responsible for binding. The intrinsic dispersity of many multivalent glycan scaffolds also limits their reproducibility and predictability. Here we make use of the structurally programmable nature of self-assembled metal coordination cages, with polyhedral metal-ion cores supporting ligand arrays of predictable sizes, to assemble a 16-membered library of perfectly monodisperse glycoclusters displaying valencies from 2 to 24 through a careful choice of ligand/metal combinations. Mono- and trisaccharides are introduced into these clusters, showing that the synthetic route is tolerant of biologically relevant glycans, including sialic acids. The cluster series demonstrates increased binding to a range of lectins as the number of glycans increases. This strategy offers an alternative to current glycomaterials for control of the valency of three-dimensional (3-D) glycan arrays, and may find application across sensing, imaging, and basic biology

Metagenomic next-generation sequencing aids the diagnosis of viral infections in febrile returning travellers

Objectives Travel-associated infections are challenging to diagnose because of the broad spectrum of potential aetiologies. As a proof-of-principle study, we used MNGS to identify viral pathogens in clinical samples from returning travellers in a single center to explore its suitability as a diagnostic tool. Methods Plasma samples from 40 returning travellers presenting with a fever of ≥38°C were sequenced using MNGS on the Illumina MiSeq platform and compared with standard-of-care diagnostic assays. Results In total, 11/40 patients were diagnosed with a viral infection. Standard of care diagnostics revealed 5 viral infections using plasma samples; dengue virus 1 (n = 2), hepatitis E (n = 1), Ebola virus (n = 1) and hepatitis A (n = 1), all of which were detected by MNGS. Three additional patients with Chikungunya virus (n = 2) and mumps virus were diagnosed by MNGS only. Respiratory infections detected by nasal/throat swabs only were not detected by MNGS of plasma. One patient had infection with malaria and mumps virus during the same admission. Conclusions MNGS analysis of plasma samples improves the sensitivity of diagnosis of viral infections and has potential as an all-in-one diagnostic test. It can be used to identify infections that have not been considered by the treating physician, co-infections and new or emerging pathogens. Summary Next generation sequencing (NGS) has potential as an all-in-one diagnostic test. In this study we used NGS to diagnose returning travellers with acute febrile illness in the UK, highlighting cases where the diagnosis was missed using standard methods

A family of externally-functionalised coordination cages

New synthetic routes are presented to derivatives of a (known) M8L12 cubic coordination cage in which a range of different substituents are attached at the C4 position of the pyridyl rings at either end of the bis(pyrazolyl-pyridine) bridging ligands. The substituents are (i) –CN groups (new ligand LCN), (ii) –CH2OCH2–CCH (containing a terminal alkyne) groups (new ligand LCC); and (iii) –(CH2OCH2)3CH2OMe (tri-ethyleneglycol monomethyl ether) groups (new ligand LPEG). The resulting functionalised ligands combine with M2+ ions (particularly Co2+, Ni2+, Cd2+) to give isostructural [M8L12]16+ cage cores bearing 24 external functional groups; the cages based on LCN (with M2+ = Cd2+) and LCC (with M2+ = Ni2+) have been crystallographically characterised. The value of these is twofold: (i) exterior nitrile or alkene substituents can provide a basis for further synthetic opportunities via ‘Click’ reactions allowing in principle a diverse range of functionalisation of the cage exterior surface; (ii) the exterior –(CH2OCH2)3CH2OMe groups substantially increase cage solubility in both water and in organic solvents, allowing binding constants of cavity-binding guests to be measured under an increased range of conditions

Inclusive Masculinities in a Working-Class Sixth Form in Northeast England

This research examines the construction of masculinity among a group of working-class boys aged sixteen to nineteen in the northeast of England. Drawing on data collected from a six-week ethnography with boys in a religious (Christian) sixth form college, this study documents how only a small minority of these boys embodied the orthodox archetype of masculinity that has traditionally been associated with working-class youth. Instead, the great majority of participants adopted attitudes and behaviors that can be categorized as a set of inclusive masculinities: They espoused positive attitudes toward homosexuality, engaged in physical tactility and emotional intimacy, and used homosexually themed language without the intent to wound or marginalize other boys. These findings pose a considerable challenge to dominant narratives on working-class masculinities; narratives that must now be reconfigured to account for the proliferation of inclusive masculinities among working-class youth

Catch a tiger snake by its tail: Differential toxicity, co-factor dependence and antivenom efficacy in a procoagulant clade of Australian venomous snakes

A paradigm of venom research is adaptive evolution of toxins as part of a predator-prey chemical arms race. This study examined differential co-factor dependence, variations relative to dietary preference, and the impact upon relative neutralisation by antivenom of the procoagulant toxins in the venoms of a clade of Australian snakes. All genera were characterised by venoms rich in factor Xa which act upon endogenous prothrombin. Examination of toxin sequences revealed an extraordinary level of conservation, which indicates that adaptive evolution is not a feature of this toxin type. Consistent with this, the venoms did not display differences on the plasma of different taxa. Examination of the prothrombin target revealed endogenous blood proteins are under extreme negative selection pressure for diversification, this in turn puts a strong negative selection pressure upon the toxins as sequence diversification could result in a drift away from the target. Thus this study reveals that adaptive evolution is not a consistent feature in toxin evolution in cases where the target is under negative selection pressure for diversification. Consistent with this high level of toxin conservation, the antivenom showed extremely high-levels of cross-reactivity. There was however a strong statistical correlation between relative degree of phospholipid-dependence and clotting time, with the least dependent venoms producing faster clotting times than the other venoms even in the presence of phospholipid. The results of this study are not only of interest to evolutionary and ecological disciplines, but also have implications for clinical toxinology

Characterisation of the surface structure of 3D printed scaffolds for cell infiltration and surgical suturing

3D printing is of great interest for tissue engineering scaffolds due to the ability to form complex geometries and control internal structures, including porosity and pore size. The porous structure of scaffolds plays an important role in cell ingrowth and nutrition infusion. Although the internal porosity and pore size of 3D printed scaffolds have been frequently studied, the surface porosity and pore size, which are critical for cell infiltration and mass transport, have not been investigated. The surface geometry can differ considerably from the internal scaffold structure depending on the 3D printing process. It is vital to be able to control the surface geometry of scaffolds as well as the internal structure to fabricate optimal architectures. This work presents a method to control the surface porosity and pore size of 3D printed scaffolds. Six scaffold designs have been printed with surface porosities ranging from 3% to 21%. We have characterised the overall scaffold porosity and surface porosity using optical microscopy and microCT. It has been found that surface porosity has a significant impact on cell infiltration and proliferation. In addition, the porosity of the surface has been found to have an effect on mechanical properties and on the forces required to penetrate the scaffold with a surgical suturing needle. To the authors' knowledge, this study is the first to investigate the surface geometry of extrusion-based 3D printed scaffolds and demonstrates the importance of surface geometry in cell infiltration and clinical manipulation

Effects of sleep disturbance on dyspnoea and impaired lung function following hospital admission due to COVID-19 in the UK:a prospective multicentre cohort study

BACKGROUND: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. METHODS: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2-7 months after hospital discharge and a later time point 10-14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). FINDINGS: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4-6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5-8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (-19%; 95% CI -20 to -16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18-39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27-41% of this effect. INTERPRETATION: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. FUNDING: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council

Ecological Meltdown in the Firth of Clyde, Scotland: Two Centuries of Change in a Coastal Marine Ecosystem

BACKGROUND: The Firth of Clyde is a large inlet of the sea that extends over 100 km into Scotland\u27s west coast. METHODS: We compiled detailed fisheries landings data for this area and combined them with historical accounts to build a picture of change due to fishing activity over the last 200 years. FINDINGS: In the early 19th century, prior to the onset of industrial fishing, the Firth of Clyde supported diverse and productive fisheries for species such as herring (Clupea harengus, Clupeidae), cod (Gadus morhua, Gadidae), haddock (Melanogrammus aeglefinus, Gadidae), turbot (Psetta maxima, Scophthalmidae) and flounder (Platichthys flesus, Pleuronectidae). The 19th century saw increased demand for fish, which encouraged more indiscriminate methods of fishing such as bottom trawling. During the 1880s, fish landings began to decline, and upon the recommendation of local fishers and scientists, the Firth of Clyde was closed to large trawling vessels in 1889. This closure remained in place until 1962 when bottom trawling for Norway lobster (Nephrops norvegicus, Nephropidae) was approved in areas more than three nautical miles from the coast. During the 1960s and 1970s, landings of bottomfish increased as trawling intensified. The trawl closure within three nautical miles of the coast was repealed in 1984 under pressure from the industry. Thereafter, bottomfish landings went into terminal decline, with all species collapsing to zero or near zero landings by the early 21st century. Herring fisheries collapsed in the 1970s as more efficient mid-water trawls and fish finders were introduced, while a fishery for mid-water saithe (Pollachius virens, Gadidae) underwent a boom and bust shortly after discovery in the late 1960s. The only commercial fisheries that remain today are for Nephrops and scallops (Pecten maximus, Pectinidae). SIGNIFICANCE: The Firth of Clyde is a marine ecosystem nearing the endpoint of overfishing, a time when no species remain that are capable of sustaining commercial catches. The evidence suggests that trawl closures helped maintain productive fisheries through the mid-20th century, and their reopening precipitated collapse of bottomfish stocks. We argue that continued intensive bottom trawling for Nephrops with fine mesh nets will prevent the recovery of other species. This once diverse and highly productive environment will only be restored if trawl closures or other protected areas are re-introduced. The Firth of Clyde represents at a small scale a process that is occurring ocean-wide today, and its experience serves as a warning to others

Effects of sleep disturbance on dyspnoea and impaired lung function following hospital admission due to COVID-19 in the UK: a prospective multicentre cohort study

BACKGROUND: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. METHODS: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2-7 months after hospital discharge and a later time point 10-14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). FINDINGS: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4-6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5-8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (-19%; 95% CI -20 to -16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18-39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27-41% of this effect. INTERPRETATION: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. FUNDING: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council