Comparative fitness analysis of proteolytic cleavage site vaccine variants in simian immunodeficiency virus

Over the past few decades, the human immunodeficiency virus and its progression to acquired immunodeficiency syndrome has become one of the most prominent global health issues. As the number of infected persons continues to grow, it is increasingly important to develop a protective vaccine to stop HIV transmission, and a cure for those already infected. Although current combination antiretroviral therapy can help patients maintain undetectable levels of the virus throughout their bodies, once the treatment is stopped, the virus will rebound. In this project, the effects of a vaccine therapy that targets the protease cleavage sites (PCS) of the HIV protease were evaluated in 16 Cynomolgus macaques. Preliminary results of the study show that in the vaccine group (n=11), a disruption to one or more of the HIV protease cleavage sites leads to a better maintenance of CD4+ T cells versus that in the control group (n=5). Furthermore, a correlation between the percentage of PCS mutations and viral load was also observed. Upon closer analysis, it was determined that the most common sites of mutation occur at PCS2 and PCS12. To assess the impact of these PCS mutations on viral fitness, we used site directed mutagenesis to introduce single amino acid mutations into a fully infectious SIV clone (SIVmac239). Ongoing studies include producing virus stocks of the SIVmac239 mutants (with multiple PCS mutations) and evaluating the viral fitness of the SIVmac239 clones in cell lines using growth competition assays. The data from this study and future studies will help provide information in the areas of vaccine and therapy development for HIV

Formation, crystal growth and colour appearance of Mimetic Tianmu glaze

WZZ thanks EPSRC for financial support on FEG-SEM equipment (EP/F019580/1).Mimetic Tianmu glaze has been synthesized and analysed by using X-ray diffraction, energy-dispersive X-ray spectroscopy, scanning electron microscopy and transmission electron microscopy. It was found that the main body of the glaze was amorphous aluminium silicate with many embedded polycrystalline spherical particles of metal oxides containing manganese, cobalt, vanadium, bismuth and tungsten. Two dimensional spinel dendrites crystals of manganese, cobalt and aluminium oxide formed on the surface of the glaze. The formation mechanism of the microstructures in the Tianmu glaze is proposed. The colour appearance of the glaze has also been discussed. It has been found that the crystal thickness dependant light interference could be an important factor for the appearance of rainbow-like colour in the glaze layer.PostprintPeer reviewe

Dendritic distributions of l\u3csub\u3eh\u3c/sub\u3e channels in experimentally-derived multi-compartment models of oriens-lacunosum/moleculare (O-LM) hippocampal interneurons

The O-LM cell type mediates feedback inhibition onto hippocampal pyramidal cells and gates information flow in the CA1. Its functions depend on the presence of voltage-gated channels (VGCs), which affect its integrative properties and response to synaptic input. Given the challenges associated with determining densities and distributions of VGCs on interneuron dendrites, we take advantage of computational modeling to consider different possibilities. In this work, we focus on hyperpolarization-activated channels (h-channels) in O-LM cells. While h-channels are known to be present in O-LM cells, it is unknown whether they are present on their dendrites. In previous work, we used ensemble modeling techniques with experimental data to obtain insights into potentially important conductance balances. We found that the best O-LM models that included uniformly distributed h-channels in the dendrites could not fully capture the “sag” response. This led us to examine activation kinetics and non-uniform distributions of h-channels in the present work. In tuning our models, we found that different kinetics and non-uniform distributions could better reproduce experimental O-LM cell responses. In contrast to CA1 pyramidal cells where higher conductance densities of h-channels occur in more distal dendrites, decreasing conductance densities of h-channels away from the soma were observed in O-LM models. Via an illustrative scenario, we showed that having dendritic h-channels clearly speeds up back-propagating action potentials in O-LM cells, unlike when h-channels are present only in the soma. Although the present results were morphology-dependent, our work shows that it should be possible to determine the distributions and characteristics of O-LM cells with recordings and morphologies from the same cell. We hypothesize that h-channels are distributed in O-LM cell dendrites and endow them with particular synaptic integration properties that shape information flow in hippocampus

Structural Basis of Cytochrome c Presentation by IEk

The COOH-terminal peptides of pigeon and moth cytochrome c, bound to mouse IEk, are two of the most thoroughly studied T cell antigens. We have solved the crystal structures of the moth peptide and a weak agonist–antagonist variant of the pigeon peptide bound to IEk. The moth peptide and all other peptides whose structures have been solved bound to IEk, have a lysine filling the p9 pocket of IEk. However, the pigeon peptide has an alanine at p9 shifting the lysine to p10. Rather than kinking to place the lysine in the anchor pocket, the pigeon peptide takes the extended course through the binding groove, which is characteristic of all other peptides bound to major histocompatibility complex (MHC) class II. Thus, unlike MHC class I, in which peptides often kink to place optimally anchoring side chains, MHC class II imposes an extended peptide conformation even at the cost of a highly conserved anchor residue. The substitution of Ser for Thr at p8 in the variant pigeon peptide induces no detectable surface change other than the loss of the side chain methyl group, despite the dramatic change in recognition by T cells. Finally, these structures can be used to interpret the many published mutational studies of these ligands and the T cell receptors that recognize them

Impact of multimorbidity count on all-cause mortality and glycaemic outcomes in people with type 2 diabetes: a systematic review protocol

Introduction: Type 2 diabetes (T2D) is a leading health priority worldwide. Multimorbidity (MM) is a term describing the co-occurrence of two or more chronic diseases or conditions. The majority of people living with T2D have MM. The relationship between MM and mortality and glycaemia in people with T2D is not clear. Methods and analysis: Medline, Embase, Cumulative Index of Nursing and Allied Health Complete, The Cochrane Library, and SCOPUS will be searched with a prespecified search strategy. The searches will be limited to quantitative empirical studies in English with no restriction on publication date. One reviewer will perform title screening and two review authors will independently screen the abstract and full texts using Covidence software, with disagreements adjudicated by a third reviewer. Data will be extracted using a using a Population, Exposure, Comparator and Outcomes framework. Two reviewers will independently extract data and undertake the risk of bias (quality) assessment. Disagreements will be resolved by consensus. A narrative synthesis of the results will be conducted and meta-analysis considered if appropriate. Quality appraisal will be undertaken using the Newcastle-Ottawa quality assessment scale and the quality of the cumulative evidence of the included studies will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. This protocol was prepared in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines to ensure the quality of our review. Ethics and dissemination: This review will synthesise the existing evidence about the impact of MM on mortality and glycaemic outcomes in people living with T2D and increase our understanding of this subject and will inform future practice and policy. Findings will be disseminated via conference presentations, social media and peer-reviewed publication

Growth mechanism of dendritic hematite via hydrolysis of ferricyanide

W.Z. thanks EPSRC for financial support to purchase the FEG SEM (EP/F019580/1).The detailed process of the hydrolysis of ferricyanide into dendritic α-Fe2O3 (hematite) crystals with snowflake-like, feather-like and leaf-like morphologies has been investigated. [Fe(CN)6]3– anions were found to polymerize into large, disordered soft matter aggregates at an early stage. The nucleation of hematite crystals took place near the surface of these aggregates via further hydrolysis. After the crystals grew to a certain size, branches started to appear. When the concentration of ferricyanide was low (i.e. 2 mM to 3.8 mM), growth was preferentially along the six equivalent directions, resulting in a flat snowflake-like shape, while high concentrations (i.e. 9 mM to 500 mM) of ferricyanide led to the growth of selective directions along the zone axes, forming a feather-like or leaf-like morphology. Highly selective adsorption and surface hydrolysis of [Fe(CN)6]3– anions on α-Fe2O3 crystals was found to be a crucial process in the formation of these novel morphologies. It was found that the polymeri- sation of ferricyanide led to a reduction of pH value and that the formation of Fe2O3 increased pH value. The pH value of the solution at the point when the branches start to grow can significantly affect the distribution of Lewis acidic sites on different surfaces and, therefore, change the growth direction. The newly established mechanism is complementary to the classical theories of crystal growth.PostprintPeer reviewe

Bioresorbable silicon electronics for transient spatiotemporal mapping of electrical activity from the cerebral cortex.

Bioresorbable silicon electronics technology offers unprecedented opportunities to deploy advanced implantable monitoring systems that eliminate risks, cost and discomfort associated with surgical extraction. Applications include postoperative monitoring and transient physiologic recording after percutaneous or minimally invasive placement of vascular, cardiac, orthopaedic, neural or other devices. We present an embodiment of these materials in both passive and actively addressed arrays of bioresorbable silicon electrodes with multiplexing capabilities, which record in vivo electrophysiological signals from the cortical surface and the subgaleal space. The devices detect normal physiologic and epileptiform activity, both in acute and chronic recordings. Comparative studies show sensor performance comparable to standard clinical systems and reduced tissue reactivity relative to conventional clinical electrocorticography (ECoG) electrodes. This technology offers general applicability in neural interfaces, with additional potential utility in treatment of disorders where transient monitoring and modulation of physiologic function, implant integrity and tissue recovery or regeneration are required

Multimorbidity, mortality, and HbA1c in type 2 diabetes: a cohort study with UK and Taiwanese cohorts

Background: There is emerging interest in multimorbidity in type 2 diabetes (T2D), which can be either concordant (T2D related) or discordant (unrelated), as a way of understanding the burden of disease in T2D. Current diabetes guidelines acknowledge the complex nature of multimorbidity, the management of which should be based on the patient’s individual clinical needs and comorbidities. However, although associations between multimorbidity, glycated haemoglobin (HbA1c), and mortality in people with T2D have been studied to some extent, significant gaps remain, particularly regarding different patterns of multimorbidity, including concordant and discordant conditions. This study explores associations between multimorbidity (total condition counts/concordant/discordant/different combinations of conditions), baseline HbA1c, and all-cause mortality in T2D. Methods and findings: We studied two longitudinal cohorts of people with T2D using the UK Biobank (n = 20,569) and the Taiwan National Diabetes Care Management Program (NDCMP) (n = 59,657). The number of conditions in addition to T2D was used to quantify total multimorbidity, concordant, and discordant counts, and the effects of different combinations of conditions were also studied. Outcomes of interest were baseline HbA1c and all-cause mortality. For the UK Biobank and Taiwan NDCMP, mean (SD) ages were 60.2 (6.8) years and 60.8 (11.3) years; 7,579 (36.8%) and 31,339 (52.5%) were female; body mass index (BMI) medians (IQR) were 30.8 (27.7, 34.8) kg/m2 and 25.6 (23.5, 28.7) kg/m2; and 2,197 (10.8%) and 9,423 (15.8) were current smokers, respectively. Increasing total and discordant multimorbidity counts were associated with lower HbA1c and increased mortality in both datasets. In Taiwan NDCMP, for those with four or more additional conditions compared with T2D only, the mean difference (95% CI) in HbA1c was −0.82% (−0.88, −0.76) p < 0.001. In UK Biobank, hazard ratios (HRs) (95% CI) for all-cause mortality in people with T2D and one, two, three, and four or more additional conditions compared with those without comorbidity were 1.20 (0.91–1.56) p < 0.001, 1.75 (1.35–2.27) p < 0.001, 2.17 (1.67–2.81) p < 0.001, and 3.14 (2.43–4.03) p < 0.001, respectively. Both concordant/discordant conditions were significantly associated with mortality; however, HRs were largest for concordant conditions. Those with four or more concordant conditions had >5 times the mortality (5.83 [4.28–7.93] p <0.001). HRs for NDCMP were similar to those from UK Biobank for all multimorbidity counts. For those with two conditions in addition to T2D, cardiovascular diseases featured in 18 of the top 20 combinations most highly associated with mortality in UK Biobank and 12 of the top combinations in the Taiwan NDCMP. In UK Biobank, a combination of coronary heart disease and heart failure in addition to T2D had the largest effect size on mortality, with a HR (95% CI) of 4.37 (3.59–5.32) p < 0.001, whereas in the Taiwan NDCMP, a combination of painful conditions and alcohol problems had the largest effect size on mortality, with an HR (95% CI) of 4.02 (3.08–5.23) p < 0.001. One limitation to note is that we were unable to model for changes in multimorbidity during our study period. Conclusions: Multimorbidity patterns associated with the highest mortality differed between UK Biobank (a population predominantly comprising people of European descent) and the Taiwan NDCMP, a predominantly ethnic Chinese population. Future research should explore the mechanisms underpinning the observed relationship between increasing multimorbidity count and reduced HbA1c alongside increased mortality in people with T2D and further examine the implications of different patterns of multimorbidity across different ethnic groups. Better understanding of these issues, especially effects of condition type, will enable more effective personalisation of care

Associations between multimorbidity and glycaemia (HbA1c) in people with type 2 diabetes: cross-sectional study in Australian general practice

Objectives: To explore the prevalence of multimorbidity as well as individual and combinations of long-term conditions (LTCs) in people with type 2 diabetes (T2D) attending Australian general practice, using electronic health record (EHR) data. We also examine the association between multimorbidity condition count (total/concordant(T2D related)/discordant(unrelated)) and glycaemia (glycated haemoglobin, HbA1c). Design: Cross-sectional study. Setting: Australian general practice. Participants: 69 718 people with T2D with a general practice encounter between 2013 and 2015 captured in the MedicineInsight database (EHR Data from 557 general practices and >3.8 million Australian patients). Primary and secondary outcome measures: Prevalence of multimorbidity, individual and combinations of LTCs. Multivariable linear regression models used to examine associations between multimorbidity counts and HbA1c (%). Results: Mean (SD) age 66.42 (12.70) years, 46.1% female and mean (SD) HbA1c 7.1 (1.4)%. More than 90% of participants with T2D were living with multimorbidity. Discordant conditions were more prevalent (83.4%) than concordant conditions (69.9 %). The three most prevalent discordant conditions were: painful conditions (55.4%), dyspepsia (31.6%) and depression (22.8%). The three most prevalent concordant conditions were hypertension (61.4%), coronary heart disease (17.1%) and chronic kidney disease (8.5%). The three most common combinations of conditions were: painful conditions and hypertension (38.8%), painful conditions and dyspepsia (23.1%) and hypertension and dyspepsia (22.7%). We found no associations between any multimorbidity counts (total, concordant and discordant) or combinations and HbA1c. Conclusions: Multimorbidity was common in our cohort of people with T2D attending Australian general practice, but was not associated with glycaemia. Although we did not explore mortality in this study, our results suggest that the increased mortality in those with multimorbidity and T2D observed in other studies may not be linked to glycaemia. Interestingly, discordant conditions were more prevalent than concordant conditions with painful conditions being the second most common comorbidity. Better understanding of the implications of different patterns of multimorbidity in people with T2D will allow more effective tailored care

Multimorbidity, glycaemic variability and time in target range in people with type 2 diabetes: a baseline analysis of the GP-OSMOTIC trial

Aims: To explore associations between multimorbidity condition counts (total; concordant (diabetes-related); discordant (unrelated to diabetes)) and glycaemia (HbA1c; glycaemic variability (GV); time in range (TIR)) using data from a randomised controlled trial examining effectiveness of continuous glucose monitoring (CGM) in people with type 2 diabetes (T2D). Methods: Cross-sectional study: 279 people with T2D using baseline data from the General Practice Optimising Structured MOnitoring To Improve Clinical outcomes (GP-OSMOTIC) trial from 25 general practices in Australia. Number of long-term conditions (LTCs) in addition to T2D used to quantify total/concordant/discordant multimorbidity counts. GV (measured by coefficient of variation (CV)) and TIR derived from CGM data. Multivariable linear regression models used to examine associations between multimorbidity counts, HbA1c (%), GV and TIR. Results: Mean (SD) age of participants 60.4 (9.9) years; 40.9% female. Multimorbidity was present in 89.2% of participants. Most prevalent comorbid LTCs: hypertension (57.4%), painful conditions (29.8%), coronary heart disease (22.6%) and depression (19.0%). No evidence of associations between multimorbidity counts, HbA1c, GV and TIR. Conclusions: While multimorbidity was common in this T2D cohort, it was not associated with HbA1c, CV or TIR. Future studies should explore factors other than glycaemia that contribute to the increased mortality observed in those with multimorbidity and T2D