Hormonal gatekeeping via the blood-brain barrier governs caste-specific behavior in ants.

Here, we reveal an unanticipated role of the blood-brain barrier (BBB) in regulating complex social behavior in ants. Using scRNA-seq, we find localization in the BBB of a key hormone-degrading enzyme called juvenile hormone esterase (Jhe), and we show that this localization governs the level of juvenile hormone (JH3) entering the brain. Manipulation of the Jhe level reprograms the brain transcriptome between ant castes. Although ant Jhe is retained and functions intracellularly within the BBB, we show that Drosophila Jhe is naturally extracellular. Heterologous expression of ant Jhe into the Drosophila BBB alters behavior in fly to mimic what is seen in ants. Most strikingly, manipulation of Jhe levels in ants reprograms complex behavior between worker castes. Our study thus uncovers a remarkable, potentially conserved role of the BBB serving as a molecular gatekeeper for a neurohormonal pathway that regulates social behavior.

Restoring Atrial T-Tubules Augments Systolic Ca Upon Recovery From Heart Failure.

BACKGROUND: Transverse (t)-tubules drive the rapid and synchronous Ca2+ rise in cardiac myocytes. The virtual complete atrial t-tubule loss in heart failure (HF) decreases Ca2+ release. It is unknown if or how atrial t-tubules can be restored and how this affects systolic Ca2+. METHODS: HF was induced in sheep by rapid ventricular pacing and recovered following termination of rapid pacing. Serial block-face scanning electron microscopy and confocal imaging were used to study t-tubule ultrastructure. Function was assessed using patch clamp, Ca2+, and confocal imaging. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and expressed in rat neonatal ventricular myocytes to determine if they altered t-tubule structure. RESULTS: Atrial t-tubules were lost in HF but reappeared following recovery from HF. Recovered t-tubules were disordered, adopting distinct morphologies with increased t-tubule length and branching. T-tubule disorder was associated with mitochondrial disorder. Recovered t-tubules were functional, triggering Ca2+ release in the cell interior. Systolic Ca2+, ICa-L, sarcoplasmic reticulum Ca2+ content, and sarcoendoplasmic reticulum Ca2+ ATPase function were restored following recovery from HF. Confocal microscopy showed fragmentation of ryanodine receptor staining and movement away from the z-line in HF, which was reversed following recovery from HF. Acute detubulation, to remove recovered t-tubules, confirmed their key role in restoration of the systolic Ca2+ transient, the rate of Ca2+ removal, and the peak L-type Ca2+ current. The abundance of telethonin and myotubularin decreased during HF and increased during recovery. Transfection with these proteins altered the density and structure of tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria. CONCLUSIONS: We show that recovery from HF restores atrial t-tubules, and this promotes recovery of ICa-L, sarcoplasmic reticulum Ca2+ content, and systolic Ca2+. We demonstrate an important role for myotubularin in t-tubule restoration. Our findings reveal a new and viable therapeutic strategy.

Mimicking superinfection exclusion disrupts alphavirus infection and transmission in the yellow fever mosquito Aedes aegypti.

Multiple viruses, including pathogenic viruses, bacteriophages, and even plant viruses, cause a phenomenon termed superinfection exclusion whereby a currently infected cell is resistant to secondary infection by the same or a closely related virus. In alphaviruses, this process is thought to be mediated, at least in part, by the viral protease (nsP2) which is responsible for processing the nonstructural polyproteins (P123 and P1234) into individual proteins (nsP1-nsP4), forming the viral replication complex. Taking a synthetic biology approach, we mimicked this naturally occurring phenomenon by generating a superinfection exclusion-like state in Aedes aegypti mosquitoes, rendering them refractory to alphavirus infection. By artificially expressing Sindbis virus (SINV) and chikungunya virus (CHIKV) nsP2 in mosquito cells and transgenic mosquitoes, we demonstrated a reduction in both SINV and CHIKV viral replication rates in cells following viral infection as well as reduced infection prevalence, viral titers, and transmission potential in mosquitoes.

Structural basis of Qng1-mediated salvage of the micronutrient queuine from queuosine-5'-monophosphate as the biological substrate.

Eukaryotic life benefits from-and ofttimes critically relies upon-the de novo biosynthesis and supply of vitamins and micronutrients from bacteria. The micronutrient queuosine (Q), derived from diet and/or the gut microbiome, is used as a source of the nucleobase queuine, which once incorporated into the anticodon of tRNA contributes to translational efficiency and accuracy. Here, we report high-resolution, substrate-bound crystal structures of the Sphaerobacter thermophilus queuine salvage protein Qng1 (formerly DUF2419) and of its human ortholog QNG1 (C9orf64), which together with biochemical and genetic evidence demonstrate its function as the hydrolase releasing queuine from queuosine-5'-monophosphate as the biological substrate. We also show that QNG1 is highly expressed in the liver, with implications for Q salvage and recycling. The essential role of this family of hydrolases in supplying queuine in eukaryotes places it at the nexus of numerous (patho)physiological processes associated with queuine deficiency, including altered metabolism, proliferation, differentiation and cancer progression.

Influence of antigen density and TLR ligands on preclinical efficacy of a VLP-based vaccine against peanut allergy.

BACKGROUND: Virus-like particle (VLP) Peanut is a novel immunotherapeutic vaccine candidate for the treatment of peanut allergy. The active pharmaceutical ingredient represents cucumber mosaic VLPs (CuMVTT -VLPs) that are genetically fused with one of the major peanut allergens, Ara h 2 (CuMVTT -Ara h 2). We previously demonstrated the immunogenicity and the protective capacity of VLP Peanut-based immunization in a murine model for peanut allergy. Moreover, a Phase I clinical trial has been initiated using VLP Peanut material manufactured following a GMP-compliant manufacturing process. Key product characterization studies were undertaken here to understand the role and contribution of critical quality attributes that translate as predictive markers of immunogenicity and protective efficacy for clinical vaccine development. METHOD: The role of prokaryotic RNA encapsulated within VLP Peanut on vaccine immunogenicity was assessed by producing a VLP Peanut batch with a reduced RNA content (VLP Peanut low RNA). Immunogenicity and peanut allergen challenge studies were conducted with VLP Peanut low RNA, as well as with VLP Peanut in WT and TLR 7 KO mice. Furthermore, mass spectrometry and SDS-PAGE based methods were used to determine Ara h 2 antigen density on the surface of VLP Peanut particles. This methodology was subsequently applied to investigate the relationship between Ara h 2 antigen density and immunogenicity of VLP Peanut. RESULTS: A TLR 7 dependent formation of Ara h 2 specific high-avidity IgG antibodies, as well as a TLR 7 dependent change in the dominant IgG subclass, was observed following VLP Peanut vaccination, while total allergen-specific IgG remained relatively unaffected. Consistently, a missing TLR 7 signal caused only a weak decrease in allergen tolerability after vaccination. In contrast, a reduced RNA content for VLP Peanut resulted in diminished total Ara h 2 specific IgG responses, followed by a significant impairment in peanut allergen tolerability. The discrepant effect on allergen tolerance caused by an absent TLR 7 signal versus a reduced RNA content is explained by the observation that VLP Peanut-derived RNA not only stimulates TLR 7 but also TLR 3. Additionally, a strong correlation was observed between the number of Ara h 2 antigens displayed on the surface of VLP Peanut particles and the vaccine's immunogenicity and protective capacity. CONCLUSIONS: Our findings demonstrate that prokaryotic RNA encapsulated within VLP Peanut, including antigen density of Ara h 2 on viral particles, are key contributors to the immunogenicity and protective capacity of the vaccine. Thus, antigenicity and RNA content are two critical quality attributes that need to be determined at the stage of manufacturing, providing robust information regarding the immunogenicity and protective capacity of VLP Peanut in the mouse which has translational relevance to the human setting.

The kinematics of amblypygid (Arachnida) pedipalps during predation: extreme elongation in raptorial appendages does not result in a proportionate increase in reach and closing speed.

The link between form and function is key to understanding the evolution of unique and/or extreme morphologies. Amblypygids, or whip spiders, are arachnids that often have highly elongated spined pedipalps. These limbs are used to strike at, and secure, prey before processing by the chelicerae. Amblypygi pedipalps are multifunctional, however, being used in courtship and contest, and vary greatly in form between species. Increased pedipalp length may improve performance during prey capture, but length could also be influenced by factors including territorial contest and sexual selection. Here, for the first time, we used high-speed videography and manual tracking to investigate kinematic differences in prey capture between amblypygid species. Across six morphologically diverse species, spanning four genera and two families, we created a total dataset of 86 trials (9-20 per species). Prey capture kinematics varied considerably between species, with differences being expressed in pedipalp joint angle ranges. In particular, maximum reach ratio did not remain constant with total pedipalp length, as geometric scaling would predict, but decreased with longer pedipalps. This suggests that taxa with the most elongated pedipalps do not deploy their potential length advantage to proportionally increase reach. Therefore, a simple mechanical explanation of increased reach does not sufficiently explain pedipalp elongation. We propose other factors to help explain this phenomenon, such as social interactions or sexual selection, which would produce an evolutionary trade-off in pedipalp length between prey capture performance and other behavioural and/or anatomical pressures.

Reactivities of acrylamide warheads toward cysteine targets: a QM/ML approach to covalent inhibitor design.

Covalent inhibition offers many advantages over non-covalent inhibition, but covalent warhead reactivity must be carefully balanced to maintain potency while avoiding unwanted side effects. While warhead reactivities are commonly measured with assays, a computational model to predict warhead reactivities could be useful for several aspects of the covalent inhibitor design process. Studies have shown correlations between covalent warhead reactivities and quantum mechanic (QM) properties that describe important aspects of the covalent reaction mechanism. However, the models from these studies are often linear regression equations and can have limitations associated with their usage. Applications of machine learning (ML) models to predict covalent warhead reactivities with QM descriptors are not extensively seen in the literature. This study uses QM descriptors, calculated at different levels of theory, to train ML models to predict reactivities of covalent acrylamide warheads. The QM/ML models are compared with linear regression models built upon the same QM descriptors and with ML models trained on structure-based features like Morgan fingerprints and RDKit descriptors. Experiments show that the QM/ML models outperform the linear regression models and the structure-based ML models, and literature test sets demonstrate the power of the QM/ML models to predict reactivities of unseen acrylamide warhead scaffolds. Ultimately, these QM/ML models are effective, computationally feasible tools that can expedite the design of new covalent inhibitors.

What should be next in lifelong posterior hypospadias: Conclusions from the 2023 ERN eUROGEN and EJP-RD networking meeting.

BACKGROUND: A congenital disease is for life. Posterior hypospadias, the severe form of hypospadias with a penoscrotal, scrotal, or perineal meatus, is a challenging condition with a major impact on lifelong quality of life. AIM: Our network meeting is aimed to identify what is currently missing in the lifelong treatment of posterior hypospadias, to improve care, quality of life, and awareness for these patients. METHODS: The network meeting "Lifelong Posterior Hypospadias" in Utrecht, The Netherlands was granted by the European Joint Programme on Rare Diseases-Networking Support Scheme. There was a combination of interactive sessions (hackathons) and lectures. This paper can be regarded as the last phase of the hackathon. RESULTS: Surgery for hypospadias remains challenging and complications may occur until adulthood. Posterior hypospadias affects sexual function, fertility, and hormonal status. Transitional care from childhood into adulthood is currently insufficiently established. Patients should be more involved in defining desired treatment approach and outcome measures. For optimal outcome evaluation standardization of data collection and registration at European level is necessary. Tissue engineering may provide a solution to the shortage of healthy tissue in posterior hypospadias. For optimal results, cooperation between basic researchers from different centers, as well as involving clinicians and patients is necessary. CONCLUSIONS: To improve outcomes for patients with posterior hypospadias, patient voices should be included and lifelong care by dedicated healthcare professionals guaranteed. Other requirements are joining forces at European level in uniform registration of outcome data and cooperation in basic research.

An epigenetic switch activates bacterial quorum sensing and horizontal transfer of an integrative and conjugative element.

Horizontal transfer of the integrative and conjugative element ICEMlSymR7A converts non-symbiotic Mesorhizobium spp. into nitrogen-fixing legume symbionts. Here, we discover subpopulations of Mesorhizobium japonicum R7A become epigenetically primed for quorum-sensing (QS) and QS-activated horizontal transfer. Isolated populations in this state termed R7A* maintained these phenotypes in laboratory culture but did not transfer the R7A* state to recipients of ICEMlSymR7A following conjugation. We previously demonstrated ICEMlSymR7A transfer and QS are repressed by the antiactivator QseM in R7A populations and that the adjacently-coded DNA-binding protein QseC represses qseM transcription. Here RNA-sequencing revealed qseM expression was repressed in R7A* cells and that RNA antisense to qseC was abundant in R7A but not R7A*. Deletion of the antisense-qseC promoter converted cells into an R7A*-like state. An adjacently coded QseC2 protein bound two operator sites and repressed antisense-qseC transcription. Plasmid overexpression of QseC2 stimulated the R7A* state, which persisted following curing of this plasmid. The epigenetic maintenance of the R7A* state required ICEMlSymR7A-encoded copies of both qseC and qseC2. Therefore, QseC and QseC2, together with their DNA-binding sites and overlapping promoters, form a stable epigenetic switch that establishes binary control over qseM transcription and primes a subpopulation of R7A cells for QS and horizontal transfer.

Deep Immune and RNA Profiling Revealed Distinct Circulating CD163+ Monocytes in Diabetes-Related Complications.

CD163, a scavenger receptor with anti-inflammatory function expressed exclusively on monocytes/macrophages, is dysregulated in cases of diabetes complications. This study aimed to characterize circulating CD163+ monocytes in the presence (D+Comps) or absence (D-Comps) of diabetes-related complications. RNA-sequencing and mass cytometry were conducted on CD163+ monocytes in adults with long-duration diabetes and D+Comps or D-Comps. Out of 10,868 differentially expressed genes identified between D+Comps and D-Comps, 885 were up-regulated and 190 were down-regulated with a ≥ 1.5-fold change. In D+Comps, 'regulation of centrosome cycle' genes were enriched 6.7-fold compared to the reference genome. MIR27A, MIR3648-1, and MIR23A, the most up-regulated and CD200R1, the most down-regulated gene, were detected in D+Comps from the list of 75 'genes of interest'. CD163+ monocytes in D+Comps had a low proportion of recruitment markers CCR5, CD11b, CD11c, CD31, and immune regulation markers CD39 and CD86. A gene-protein network identified down-regulated TLR4 and CD11b as 'hub-nodes'. In conclusion, this study reports novel insights into CD163+ monocyte dysregulation in diabetes-related complications. Enriched centrosome cycle genes and up-regulated miRNAs linked to apoptosis, coupled with down-regulated monocyte activation, recruitment, and immune regulation, suggest functionally distinct CD163+ monocytes in cases of diabetes complications. Further investigation is needed to confirm their role in diabetes-related tissue damage.

The next generation virus-like particle platform for the treatment of peanut allergy.

BACKGROUND: Allergy to peanut is one of the leading causes of anaphylactic reactions among food allergic patients. Immunization against peanut allergy with a safe and protective vaccine holds a promise to induce durable protection against anaphylaxis caused by exposure to peanut. A novel vaccine candidate (VLP Peanut), based on virus-like particles (VLPs), is described here for the treatment of peanut allergy. METHODS AND RESULTS: VLP Peanut consists of two proteins: a capsid subunit derived from Cucumber mosaic virus engineered with a universal T-cell epitope (CuMVTT ) and a CuMVTT subunit fused with peanut allergen Ara h 2 (CuMVTT -Ara h 2), forming mosaic VLPs. Immunizations with VLP Peanut in both naïve and peanut-sensitized mice resulted in a significant anti-Ara h 2 IgG response. Local and systemic protection induced by VLP Peanut were established in mouse models for peanut allergy following prophylactic, therapeutic, and passive immunizations. Inhibition of FcγRIIb function resulted in a loss of protection, confirming the crucial role of the receptor in conferring cross protection against peanut allergens other than Ara h 2. CONCLUSION: VLP Peanut can be delivered to peanut-sensitized mice without triggering allergic reactions, while remaining highly immunogenic and offering protection against all peanut allergens. In addition, vaccination ablates allergic symptoms upon allergen challenge. Moreover, the prophylactic immunization setting conferred the protection against subsequent peanut-induced anaphylaxis, showing the potential for preventive vaccination. This highlights the effectiveness of VLP Peanut as a prospective break-through immunotherapy vaccine candidate toward peanut allergy. VLP Peanut has now entered clinical development with the study PROTECT.

Leveraging Advanced In Silico Techniques in Early Drug Discovery: A Study of Potent Small-Molecule YAP-TEAD PPI Disruptors.

Disruption of the YAP-TEAD protein-protein interaction is an attractive therapeutic strategy in oncology to suppress tumor progression and cancer metastasis. YAP binds to TEAD at a large flat binding interface (∼3500 Å2) devoid of a well-defined druggable pocket, so it has been difficult to design low-molecular-weight compounds to abrogate this protein-protein interaction directly. Recently, work by Furet and coworkers (ChemMedChem 2022, DOI: 10.1002/cmdc.202200303) reported the discovery of the first class of small molecules able to efficiently disrupt the transcriptional activity of TEAD by binding to a specific interaction site of the YAP-TEAD binding interface. Using high-throughput in silico docking, they identified a virtual screening hit from a hot spot derived from their previously rationally designed peptidic inhibitor. Structure-based drug design efforts led to the optimization of the hit compound into a potent lead candidate. Given advances in rapid high-throughput screening and rational approaches to peptidic ligand discovery for challenging targets, we analyzed the pharmacophore features involved in transferring from the peptidic to small-molecule inhibitor that could enable small-molecule discovery for such targets. Here, we show retrospectively that pharmacophore analysis augmented by solvation analysis of molecular dynamics trajectories can guide the designs, while binding free energy calculations provide greater insight into the binding conformation and energetics accompanying the association event. The computed binding free energy estimates agree well with experimental findings and offer useful insight into structural determinants that influence ligand binding to the TEAD interaction surface, even for such a shallow binding site. Taken together, our results demonstrates the utility of advanced in silico methods in structure-based design efforts for difficult-to-drug targets such as the YAP-TEAD transcription factor complex.

A HTA of what? Reframing through including patient perspectives in health technology assessment processes.

OBJECTIVES: Despite increasing emphasis on the inclusion of patient input in health technology assessment (HTA) in Europe in particular, questions remain as to the integration of patient insight alongside other HTA inputs. This paper aims to explore how HTA processes, while ensuring the scientific quality of assessments, "make do" with patient knowledge elicited through patients' involvement mechanisms. METHODS: The qualitative study analyzed institutional HTA and patient involvement in four European country contexts. We combined documentary analysis with interviews with HTA professionals, patient organizations, and health technology industry representatives, complemented with observational findings made during a research stay at an HTA agency. RESULTS: We present three vignettes which showcase how different parameters of assessment become reframed upon the positioning of patient knowledge alongside other forms of evidence and expertise. Each vignette explores patients' involvement during an assessment of a different type of technology and at a different stage of the HTA process. First, cost-effectiveness considerations were reframed during an appraisal of a rare disease medicine based on patient and clinician input regarding its treatment pathway; in the second vignette reframing amounted to what counts as a meaningful outcome measure for a glucose monitoring device; in the third, evaluating pediatric transplantation services involved reframing an option's appropriateness from a question of moral to one of legal acceptability. CONCLUSIONS: Making do with patient knowledge in HTA involves reframing of what is being assessed. Conceptualizing patients' involvement in this way helps us to consider the inclusion of patient knowledge not as complementary to, but as something that can transform the assessment process.

Preseason Body Composition Is Associated With In-season Player Availability in Elite Male Australian Footballers.

ABSTRACT: McCaskie, CJ, Sim, M, Newton, RU, Heasman, J, Rogalski, B, and Hart, NH. Preseason body composition is associated with in-season player availability in elite male Australian footballers. J Strength Cond Res 37(5): 1089-1095, 2023-The purpose of this study was to examine whether end of preseason body composition characteristics was associated with in-season match availability and injury. Sixty ( n = 60) elite Australian football players had body composition characteristics assessed using dual-energy X-ray absorptiometry across 3 seasons (2016, 2018, and 2021). Match availability and injury were recorded throughout each season. Pearson's correlations were calculated to assess the associations between body composition and in-season match availability and injury. Logistic regression models were used to assess the odds of missing games as a result of injury throughout a season. Regional lean soft tissue mass asymmetry and its relationship to injury and availability was explored. Statistical significance was set at p ≤ 0.05. Body composition characteristics expressed as relative values seemed to be more highly associated with in-season availability and injury than characteristics expressed as absolute values. Players with lower relative fat mass (FM) (<12.1% total body FM) were available for 89.7% of in-season matches compared with 80.7% for players with higher relative FM (>12.1% total body FM). Subsequently, players with higher relative FM had 3.3-3.5 times greater odds of missing one game to injury (odds ratio [OR] = 3.33; 95% confidence interval [CI] = 1.00-11.14; p ≤ 0.05) and missing 2 or more games to injury (OR = 3.50; 95% CI = 1.20-10.20; p ≤ 0.05) throughout a season compared with players with lower relative FM. Higher proportions of fat mass may accelerate the onset of fatigue and place players at a greater risk of injury. Reducing players' FM across the preseason phase should be a key aim for practitioners to reduce the odds of injury throughout the competitive season.

Multi-Excitation Raman Spectroscopy for Label-Free, Strain-Level Characterization of Bacterial Pathogens in Artificial Sputum Media.

The current methods for diagnosis of acute and chronic infections are complex and skill-intensive. For complex clinical biofilm infections, it can take days from collecting and processing a patient's sample to achieving a result. These aspects place a significant burden on healthcare providers, delay treatment, and can lead to adverse patient outcomes. We report the development and application of a novel multi-excitation Raman spectroscopy-based methodology for the label-free and non-invasive detection of microbial pathogens that can be used with unprocessed clinical samples directly and provide rapid data to inform diagnosis by a medical professional. The method relies on the differential excitation of non-resonant and resonant molecular components in bacterial cells to enhance the molecular finger-printing capability to obtain strain-level distinction in bacterial species. Here, we use this strategy to detect and characterize the respiratory pathogens Pseudomonas aeruginosa and Staphylococcus aureus as typical infectious agents associated with cystic fibrosis. Planktonic specimens were analyzed both in isolation and in artificial sputum media. The resonance Raman components, excited at different wavelengths, were characterized as carotenoids and porphyrins. By combining the more informative multi-excitation Raman spectra with multivariate analysis (support vector machine) the accuracy was found to be 99.75% for both species (across all strains), including 100% accuracy for drug-sensitive and drug-resistant S. aureus. The results demonstrate that our methodology based on multi-excitation Raman spectroscopy can underpin the development of a powerful platform for the rapid and reagentless detection of clinical pathogens to support diagnosis by a medical expert, in this case relevant to cystic fibrosis. Such a platform could provide translatable diagnostic solutions in a variety of disease areas and also be utilized for the rapid detection of anti-microbial resistance.

Monitoring plant water status via static uniaxial compression of the leaf lamina.

Turgor pressure is an essential, but difficult to measure indicator of plant water status. Turgor has been quantified by localized compression of cells or tissues, but a simple method to perform these measurements is lacking. We hypothesized that changes in leaf turgidity can be monitored by uniaxially compressing the leaf lamina and measuring the mechanical stress under a constrained thickness (stress relaxation) and that changes in leaf water content can be monitored by measuring the leaf thickness under constant mechanical stress. Using a simple, custom-built leaf squeeze-flow rheometer, we performed different compression tests on leaves from 13 plant species. The mechanical stress measured during stress relaxation was correlated with leaf bulk turgor pressure (R2 > 0.95) and thus with balancing pressure (R2 > 0.94); the leaf thickness measured under constant mechanical stress was correlated with relative water content (R2 > 0.74). The coefficients of these relationships were related to the leaf bulk osmotic pressure at the turgor-loss point. An idealized average-cell model suggests that, under isothermal conditions, the stationary bulk modulus during compression is largely determined by the bulk osmotic pressure. Our study presents an inexpensive, accessible and automatable method to monitor plant water status noninvasively.

Mid-infrared silicon-on-insulator waveguides with single-mode propagation over an octave of frequency.

Increasing the working optical bandwidth of a photonic circuit is important for many applications, in particular chemical sensing at mid-infrared wavelengths. This useful bandwidth is not only limited by the transparency range of waveguide materials, but also the range over which a waveguide is single or multimoded for predictable circuit behaviour. In this work, we show the first experimental demonstration of "endlessly single-mode" waveguiding in silicon photonics. Silicon-on-insulator waveguides were designed, fabricated and characterised at 1.95 µm and 3.80 µm. The waveguides were shown to support low-loss propagation (1.46 ± 0.13 dB/cm loss at 1.95 µm and 1.55 ± 0.35 dB/cm at 3.80 µm) and single-mode propagation was confirmed at 1.95 µm, meaning that only the fundamental mode was present over the wavelength range 1.95 - 3.80 µm. We also present the prospects for the use of these waveguides in sensing applications.

Insulin antibodies are prevalent in adults with type 1 diabetes referred for islet cell transplantation and are modified by islet transplantation and immunosuppression: an Australian experience.

We have analysed insulin antibodies in 149 adults with type 1 diabetes and 2859 people without diabetes. We have determined that insulin antibody levels are higher in adults with, versus without, diabetes and that the levels are falling, and more patients are becoming antibody-negative post islet cell transplantation.

N 1-Methylpseudouridine substitution enhances the performance of synthetic mRNA switches in cells.

Synthetic messenger RNA (mRNA) tools often use pseudouridine and 5-methyl cytidine as substitutions for uridine and cytidine to avoid the immune response and cytotoxicity induced by introducing mRNA into cells. However, the influence of base modifications on the functionality of the RNA tools is poorly understood. Here we show that synthetic mRNA switches containing N1-methylpseudouridine (m1Ψ) as a substitution of uridine substantially out-performed all other modified bases studied, exhibiting enhanced microRNA and protein sensitivity, better cell-type separation ability, and comparably low immune stimulation. We found that the observed phenomena stem from the high protein expression from m1Ψ containing mRNA and efficient translational repression in the presence of target microRNAs or proteins. In addition, synthetic gene circuits with m1Ψ significantly improve performance in cells. These findings indicate that synthetic mRNAs with m1Ψ modification have enormous potentials in the research and application of biofunctional RNA tools.

Bypassing the nearest emergency department for a more distant neurosurgical centre in traumatic brain injury patients.

BACKGROUND AND OBJECTIVE: Major trauma triage within regional trauma networks (RTN) select patients with suspected TBI for bypass to specialist neuroscience centres (SNC), expediting neurosurgical care but may delay resuscitation. This comparative effectiveness study assessed the impact of this strategy on the risk adjusted hospital survival rates of patients confirmed to have intracranial injury on brain computed tomography (CT) scan. METHOD: A retrospective cohort study was conducted using Trauma Audit and Research Network trauma registry data. Adult patients with a TBI on CT scan were included if they presented between June 2015 to February 2016 to SNCs or non-specialist acute hospitals (NSAH) in the North of England (South Cumbria, Lancashire and the North East Region). Patients were identified as having bypassed a nearer NSAH emergency department (ED) to a SNC using google maps. Their standardised excess survival rate was compared to TBI patients who received primary treatment at a NSAH. A multivariate logistic regression model predicting 30-day survival after TBI (Ps14n)1 was used to adjust for variation in casemix between cohorts. STUDY DESIGN AND RESULTS: 355 patients met the study inclusion criteria, with 89/355 (25%) of TBI patients bypassing a nearer NSAH to a SNC, and 266/355 (75%) receiving primary treatment at an NSAH. The median severity of intracranial injury was equivalent (median Head Abbreviated Injury Scale 4 (IQR 4-5) in each group. There was no statistically significant difference in the standardised excess survival rate between the two cohorts; +6.15% for bypass (95% CI -1.24% to +13.55%) versus -1.12% for non-bypass (95% CI -4.51% to +2.25%). CONCLUSION AND FUTURE RESEARCH: No statistically significant survival benefit was identified for TBI patients who bypassed the nearest ED to attend a SNC compared to those receiving treatment at the nearest NSAH, however a clinically significant 7% excess survival rate merits a larger study.