The antimicrobial peptide Ab-Cath, is a promising candidate for development as treatment for antimicrobial resistant (AMR) bacterial infections. Future clinical use is hampered by Ab-Cath's cationic ...peptidic nature and limited therapeutic window. Here, we evaluated hyaluronic acid-based nanogels for encapsulation of Ab-Cath to circumvent these limitations. Using microfluidics, monodispersed anionic nanogels of 156–232 nm encapsulating >99 % Ab-Cath were prepared. Unprecedented, lyophilization using polyvinyl alcohol and dextran-40 provided Ab-Cath nanogel protection and allowed easy dose adjustment. Lyophilized and redispersed Ab-Cath nanogels were as effective as Ab-Cath solution in killing AMR Staphylococcus aureus, Acinetobacter baumannii and Escherichia coli in biological fluids, and in reducing S. aureus and A. baumannii biofilms. Importantly, encapsulation of Ab-Cath in nanogels reduced Ab-Cath's cytotoxic effects on human fibroblasts by ≥10-fold. Moreover, cutaneous application of Ab-Cath nanogels eliminated bacteria colonizing 3D human skin. These findings affirm the use of nanogels to increase the selectivity index of antimicrobial peptides.
The antimicrobial peptide Ab-Cath was encapsulated in octenyl succinic anhydride-modified hyaluronic acid nanogels to improve its selectivity index. A lyophilization method was developed using polyvinyl alcohol or dextran-40 to protect the Ab-Cath nanogels from freezing, dehydration and rehydration stresses. Next, the morphology and physicochemical characteristics of lyophilized and redispersed nanogels were studied. Bactericidal, anti-biofilm and cytotoxic activities of lyophilized Ab-Cath nanogels and of the peptide in solution were assessed in vitro. Results show that encapsulation of Ab-Cath in nanogels reduces the peptide's cytotoxicity, while maintaining its antibacterial properties, thus improving the overall selectivity index of this peptide. Display omitted
•Ab-Cath is a snake-derived cathelicidin with good antibacterial activities.•Encapsulation in OSA-HA nanogels doesn't affect Ab-Cath's antibacterial activities.•Encapsulation in OSA-HA nanogels reduces Ab-Cath's cytotoxicity.•PVA and dextran-40 protect Ab-Cath nanogels during lyophilization.
Developmental periods in early life may be particularly vulnerable to impacts of environmental exposures. Human research on this topic has generally focused on single exposure-health effect ...relationships. The "exposome" concept encompasses the totality of exposures from conception onward, complementing the genome.
The Human Early-Life Exposome (HELIX) project is a new collaborative research project that aims to implement novel exposure assessment and biomarker methods to characterize early-life exposure to multiple environmental factors and associate these with omics biomarkers and child health outcomes, thus characterizing the "early-life exposome." Here we describe the general design of the project.
In six existing birth cohort studies in Europe, HELIX will estimate prenatal and postnatal exposure to a broad range of chemical and physical exposures. Exposure models will be developed for the full cohorts totaling 32,000 mother-child pairs, and biomarkers will be measured in a subset of 1,200 mother-child pairs. Nested repeat-sampling panel studies (n = 150) will collect data on biomarker variability, use smartphones to assess mobility and physical activity, and perform personal exposure monitoring. Omics techniques will determine molecular profiles (metabolome, proteome, transcriptome, epigenome) associated with exposures. Statistical methods for multiple exposures will provide exposure-response estimates for fetal and child growth, obesity, neurodevelopment, and respiratory outcomes. A health impact assessment exercise will evaluate risks and benefits of combined exposures.
HELIX is one of the first attempts to describe the early-life exposome of European populations and unravel its relation to omics markers and health in childhood. As proof of concept, it will form an important first step toward the life-course exposome.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Despite vaccination since the 1950s, pertussis has persisted and resurged. It remains a major cause of infant death worldwide and is the most prevalent vaccine-preventable disease in developed ...countries. The resurgence of pertussis has been associated with the expansion of Bordetella pertussis strains with a novel allele for the pertussis toxin (Ptx) promoter, ptxP3, which have replaced resident ptxP1 strains. Compared to ptxP1 strains, ptxP3 produce more Ptx resulting in increased virulence and immune suppression. To elucidate how B. pertussis has adapted to vaccination, we compared genome sequences of two ptxP3 strains with four strains isolated before and after the introduction vaccination.
The distribution of SNPs in regions involved in transcription and translation suggested that changes in gene regulation play an important role in adaptation. No evidence was found for acquisition of novel genes. Modern strains differed significantly from prevaccination strains, both phylogenetically and with respect to particular alleles. The ptxP3 strains were found to have diverged recently from modern ptxP1 strains. Differences between ptxP3 and modern ptxP1 strains included SNPs in a number of pathogenicity-associated genes. Further, both gene inactivation and reactivation was observed in ptxP3 strains relative to modern ptxP1 strains.
Our work suggests that B. pertussis adapted by successive accumulation of SNPs and by gene (in)activation. In particular changes in gene regulation may have played a role in adaptation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Vertically propagating linear wave calculations using realistic equatorial buoyancy profiles are presented. The percentages vary widely depending upon the buoyancy profile and the equivalent depth ...but can be as low as 10% on average for equivalent depths between 1 cm and 1 m if the thermocline is sharp. This means that models with constant or weak thermocline buoyancy profiles, are very unrealistic in this respect. Another conclusion is that the observed, very low-frequency, small vertical-scale deep jets cannot be explained by linear wave theory as caused by surface forcing.
PurposeEssential to exposome research is the collection of data on many environmental exposures from different domains in the same subjects. The aim of the Human Early Life Exposome (HELIX) study was ...to measure and describe multiple environmental exposures during early life (pregnancy and childhood) in a prospective cohort and associate these exposures with molecular omics signatures and child health outcomes. Here, we describe recruitment, measurements available and baseline data of the HELIX study populations.ParticipantsThe HELIX study represents a collaborative project across six established and ongoing longitudinal population-based birth cohort studies in six European countries (France, Greece, Lithuania, Norway, Spain and the UK). HELIX used a multilevel study design with the entire study population totalling 31 472 mother-child pairs, recruited during pregnancy, in the six existing cohorts (first level); a subcohort of 1301 mother-child pairs where biomarkers, omics signatures and child health outcomes were measured at age 6–11 years (second level) and repeat-sampling panel studies with around 150 children and 150 pregnant women aimed at collecting personal exposure data (third level).Findings to dateCohort data include urban environment, hazardous substances and lifestyle-related exposures for women during pregnancy and their offspring from birth until 6–11 years. Common, standardised protocols were used to collect biological samples, measure exposure biomarkers and omics signatures and assess child health across the six cohorts. Baseline data of the cohort show substantial variation in health outcomes and determinants between the six countries, for example, in family affluence levels, tobacco smoking, physical activity, dietary habits and prevalence of childhood obesity, asthma, allergies and attention deficit hyperactivity disorder.Future plansHELIX study results will inform on the early life exposome and its association with molecular omics signatures and child health outcomes. Cohort data are accessible for future research involving researchers external to the project.
Recently, using a deep learning approach, the novel antibiotic halicin was discovered. We compared the antibacterial activities of two novel bactericidal antimicrobial agents, i.e., the synthetic ...antibacterial and antibiofilm peptide (SAAP)-148 with this antibiotic halicin. Results revealed that SAAP-148 was more effective than halicin in killing planktonic bacteria of antimicrobial-resistant (AMR)
and
, especially in biologically relevant media, such as plasma and urine, and in 3D human infection models. Surprisingly, SAAP-148 and halicin were equally effective against these bacteria residing in immature and mature biofilms. As their modes of action differ, potential favorable interactions between SAAP-148 and halicin were investigated. For some specific strains of AMR
and
synergism between these agents was observed, whereas for other strains, additive interactions were noted. These favorable interactions were confirmed for AMR
in a 3D human bladder infection model and AMR
in a 3D human epidermal infection model. Together, combinations of these two novel antimicrobial agents hold promise as an innovative treatment for infections not effectively treatable with current antibiotics.
A linear, periodic model using the long-wave approximation on the equatorial β-plane is forced by the annual cycle of zonal wind stress from the Pacific Ocean. The forcing is deduced from the monthly ...data set of Hellerman and Rosenstein. The model results are compared with
observations of the annual cycle which are mainly of temperature in the upper central Pacific Ocean from the Hawaii-Tahiti shuttle experiment. The agreement is good in phase, but poor in amplitude. The effect on model results of different friction assumptions and coefficients shows that no
tuning of the parameters significantly improves the comparison with observations. The model is also used to study the effects of the forcing function, a sharp thermocline and friction which are all very important in determining the energy distribution below the thermocline. It is shown that
beams occur only in the unphysical situation of inviscid flow with simple forms for the forcing function. The poor comparison with observations is used to draw conclusions about the shortcomings of present linear, equatorial models. They are: the buoyancy frequency can only be a function of
depth, and the friction assumptions, which keep the vertical modes independent, have unrealistic profiles with depth and do not give realistic amplitudes both in the upper ocean and below the thermocline.
A model of the tropical ocean and global atmosphere is described. It consists of an aqua-planet form of version one of the NCAR Community Climate Model coupled to a primitive equation model for the ...upper tropical ocean in a rectangular basin. A 24-year simulation is described that has almost no climate drift, a good simulation of the mean temperature gradient across the ocean, but smaller than observed annual and interannual variability. The coupled model is analyzed to see where it occurs on the schematic bifurcation diagram of Neelin. In years 9–16 of the simulation there is a dominant oscillation with a period of two years. The spatial pattern of this oscillation shows up clearly in the first empirical orthogonal function calculated from monthly averages of sea surface temperature anomalies. A series of 19 model-twin predictability experiments were carried out with the initial perturbation being a very small change in the ocean temperature field. The correlation coefficient of monthly sea surface temperature anomalies from these model-twin experiments decreases rapidly over the first 6 months and after that, more slowly, showing that there is some predictability out to a year. The predictability times are marginally increased if only the coefficient of the first empirical orthogonal function of monthly averaged sea surface temperature anomalies or NIN03 sea surface temperature is predicted. There is some evidence to indicate that it is easier to predict the onset of a model warm event than to predict the onset of a model cold event. More detailed analysis of the first model-twin experiment shows that the initial divergence in the integrations is a change at day 6 in the incoming solar radiation due to a change in the atmospheric model clouds. The dominant early change in sea surface temperature occurs by this change in radiative heat flux. If the cloud feedback is set to zero, then the first changes are delayed to day 12 and occur in the evaporative and sensible heat fluxes and in the atmospheric wind stress. In this case the dominant early change to sea surface temperature is by advection due to the changed wind stress.
Procedures are developed for calculating effects of western boundaries of arbitrary geometry on low-frequency equatorial waves. We show that the mass flux incident at the coast is all returned ...eastward by equatorial Kelvin waves. Short Rossby waves generated as part of the reflection
serve only to redistribute mass along the coast. For the case of a uniformly sloping coast we present formulae and graphical results for the amplitude of the equatorial Kelvin wave reflected at the coast due to incident free Rossby waves. Results are shown to depend on the single parameter
γω where γ is the slope of the coast and ω is the nondimensional frequency. Similar results are presented for a special class of forced problems. Possible implications for equatorial currents in the Indian Ocean are discussed.
PDF
