99 research outputs found
Progress in human picornavirus research: New findings from the AIROPico consortium
Several research groups in Europe are active on different aspects of human picornavirus research. The AIROPico
(Academia-Industry R&D Opportunities for Picornaviruses) consortium combined the disciplines of pathogenesis, diagnostics and therapy development in order to fill the gaps in our understanding of how picornaviruses
cause human disease and how to combat them. AIROPico was the first EU consortium dedicated to human
picornavirus research and development, and has largely accelerated and improved R&D on picornavirus biology,
diagnostics and therapy. In this article, we present the progress on pathogenesis, diagnostics and treatment
strategy developments for human picornaviruses resulting from the structured, translational research approach
of the AIROPico consortium. We here summarize new insights in protection against infection by maternal or
cross-protective antibodies, the visualisation of interactions between virus and neutralizing antibodies by
cryoEM structural imaging, and the outcomes from a picornavirus-infected human 3D organoid. Progress in
molecular detection and a fast typing assay for rhinovirus species are presented, as well as the identification of
new compounds potentially interesting as therapeutic compounds.</p
Magnetism, FeS colloids, and Origins of Life
A number of features of living systems: reversible interactions and weak
bonds underlying motor-dynamics; gel-sol transitions; cellular connected
fractal organization; asymmetry in interactions and organization; quantum
coherent phenomena; to name some, can have a natural accounting via
interactions, which we therefore seek to incorporate by expanding the horizons
of `chemistry-only' approaches to the origins of life. It is suggested that the
magnetic 'face' of the minerals from the inorganic world, recognized to have
played a pivotal role in initiating Life, may throw light on some of these
issues. A magnetic environment in the form of rocks in the Hadean Ocean could
have enabled the accretion and therefore an ordered confinement of
super-paramagnetic colloids within a structured phase. A moderate H-field can
help magnetic nano-particles to not only overcome thermal fluctuations but also
harness them. Such controlled dynamics brings in the possibility of accessing
quantum effects, which together with frustrations in magnetic ordering and
hysteresis (a natural mechanism for a primitive memory) could throw light on
the birth of biological information which, as Abel argues, requires a
combination of order and complexity. This scenario gains strength from
observations of scale-free framboidal forms of the greigite mineral, with a
magnetic basis of assembly. And greigite's metabolic potential plays a key role
in the mound scenario of Russell and coworkers-an expansion of which is
suggested for including magnetism.Comment: 42 pages, 5 figures, to be published in A.R. Memorial volume, Ed
Krishnaswami Alladi, Springer 201
Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand.
OBJECTIVE: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. DESIGN: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. METHODS: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. RESULTS: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean. CONCLUSION: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age
Biochemical Comparison of Anopheles gambiae and Human NADPH P450 Reductases Reveals Different 2′-5′-ADP and FMN Binding Traits
NADPH-cytochrome P450 oxidoreductase (CPR) plays a central role in chemical
detoxification and insecticide resistance in Anopheles gambiae,
the major vector for malaria. Anopheles gambiae CPR (AgCPR) was
initially expressed in Eschericia coli but failed to bind
2′, 5′-ADP Sepharose. To investigate this unusual trait, we
expressed and purified a truncated histidine-tagged version for side-by-side
comparisons with human CPR. Close functional similarities were found with
respect to the steady state kinetics of cytochrome c reduction,
with rates (kcat) of 105
s−1 and 88 s−1, respectively, for mosquito
and human CPR. However, the inhibitory effects of 2′,5′-ADP on
activity were different; the IC50 value of AgCPR for 2′,
5′ –ADP was significantly higher (6–10 fold) than human CPR
(hCPR) in both phosphate and phosphate-free buffer, indicative of a decrease in
affinity for 2′, 5′- ADP. This was confirmed by isothermal titration
calorimetry where binding of 2′,5′-ADP to AgCPR
(Kd = 410±18 nM) was
∼10 fold weaker than human CPR
(Kd = 38 nM). Characterisation
of the individual AgFMN binding domain revealed much weaker binding of FMN
(Kd = 83±2.0 nM) than the equivalent
human domain (Kd = 23±0.9 nM).
Furthermore, AgCPR was an order of magnitude more sensitive than hCPR to the
reductase inhibitor diphenyliodonium chloride
(IC50 = 28 µM±2 and 361±31
µM respectively). Taken together, these results reveal unusual biochemical
differences between mosquito CPR and the human form in the binding of small
molecules that may aid the development of ‘smart’ insecticides and
synergists that selectively target mosquito CPR
External validation of the PAGE-B score for HCC risk prediction in people living with HIV/HBV coinfection
Background & Aims: HBV coinfection is common among people living with HIV (PLWH) and is the most important cause of hepatocellular carcinoma (HCC). While risk prediction tools for HCC have been validated in patients with HBV monoinfection, they have not been evaluated in PLWH. Thus, we performed an external validation of PAGE-B in people with HIV/HBV coinfection. Methods: We included data on PLWH from four European cohorts who were positive for HBsAg and did not have HCC before starting tenofovir. We estimated the predictive performance of PAGE-B for HCC occurrence over 15 years in patients receiving tenofovir-containing antiretroviral therapy. Model discrimination was assessed after multiple imputation using Cox regression with the prognostic index as a covariate, and by calculating Harrell's c-index. Calibration was assessed by comparing our cumulative incidence with the PAGE-B derivation study using Kaplan-Meier curves. Results: In total, 2,963 individuals with HIV/HBV coinfection on tenofovir-containing antiretroviral therapy were included. PAGE-B was <10 in 26.5%, 10–17 in 57.7%, and ≥18 in 15.7% of patients. Within a median follow-up of 9.6 years, HCC occurred in 68 individuals (2.58/1,000 patient-years, 95% CI 2.03–3.27). The regression slope of the prognostic index for developing HCC within 15 years was 0.93 (95% CI 0.61–1.25), and the pooled c-index was 0.77 (range 0.73–0.80), both indicating good model discrimination. The cumulative incidence of HCC was lower in our study compared to the derivation study. A PAGE-B cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. Restricting efforts to individuals with a PAGE-B of ≥10 would spare unnecessary HCC screening in 27% of individuals. Conclusions: For individuals with HIV/HBV coinfection, PAGE-B is a valid tool to determine the need for HCC screening. Impact and implications: Chronic HBV infection is the most important cause of hepatocellular carcinoma (HCC) among people living with HIV. Valid risk prediction may enable better targeting of HCC screening efforts to high-risk individuals. We aimed to validate PAGE-B, a risk prediction tool that is based on age, sex, and platelets, in 2,963 individuals with HIV/HBV coinfection who received tenofovir-containing antiretroviral therapy. In the present study, PAGE-B showed good discrimination, adequate calibration, and a cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. These results indicate that PAGE-B is a simple and valid risk prediction tool to determine the need for HCC screening among people living with HIV and HBV
Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand
Objective: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV.
Design: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand.
Methods: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters.
Results: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean.
Conclusion: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age
Malignancies among children and young people with HIV in Western and Eastern Europe and Thailand
A highly reactive precursor in the iron sulfide system
Iron sulfur (Fe–S) phases have been implicated in the emergence of life on early Earth due to their catalytic role in the synthesis of prebiotic molecules. Similarly, Fe–S phases are currently of high interest in the development of green catalysts and energy storage. Here we report the synthesis and structure of a nanoparticulate phase (FeSnano) that is a necessary solid-phase precursor to the conventionally assumed initial precipitate in the iron sulfide system, mackinawite. The structure of FeSnano contains tetrahedral iron, which is compensated by monosulfide and polysulfide sulfur species. These together dramatically affect the stability and enhance the reactivity of FeSnano
Recommendations for enterovirus diagnostics and characterisation within and beyond Europe
Enteroviruses (EV) can cause severe neurological and respiratory infections, and occasionally lead to devastating outbreaks as previously demonstrated with EV-A71 and EV-D68 in Europe. However, these infections are still often underdiagnosed and EV typing data is not currently collected at European level. In order to improve EV diagnostics, collate data on severe EV infections and monitor the circulation of EV types, we have established European non-polio enterovirus network (ENPEN). First task of this cross-border network has been to ensure prompt and adequate diagnosis of these infections in Europe, and hence we present recommendations for nonpolio EV detection and typing based on the consensus view of this multidisciplinary team including experts from over 20 European countries. We recommend that respiratory and stool samples in addition to cerebrospinal fluid (CSF) and blood samples are submitted for EV testing from patients with suspected neurological infections. This is vital since viruses like EV-D68 are rarely detectable in CSF or stool samples. Furthermore, reverse transcriptase PCR (RT-PCR) targeting the 5' noncoding regions (5' NCR) should be used for diagnosis of EVs due to their sensitivity, specificity and short turnaround time. Sequencing of the VP1 capsid protein gene is recommended for EV typing; EV typing cannot be based on the 5' NCR sequences due to frequent recombination events and should not rely on virus isolation. Effective and standardized laboratory diagnostics and characterisation of circulating virus strains are the first step towards effective and continuous surveillance activities, which in turn will be used to provide better estimation on EV disease burden
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