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Thermoresponsive engineered emulsions stabilised with branched copolymer surfactants for nasal drug delivery of molecular therapeutics
Get PDFNovel branched copolymer surfactants (BCS) allow the formation of oil-in-water emulsions that exhibit a temperature-induced liquid-to-gel transition. If the temperature of this transition is between room and body temperature (ca 25 and 37 °C, respectively), then the emulsions form a gel in situ upon contact with the body. A major advantage of this in situ gelation is the potential to manipulate the materials at room temperature in the low viscosity liquid state, then administer them to the body to initiate a switch to a retentive gel state, which could be used to deliver drugs to challenging sites such as the nasal mucosa. There are, however, several important factors which have not been explored for thermoresponsive BCS-stabilised emulsions to progress their use towards this application. Neither the delivery of drugs from the materials, the retention on tissue, nor the impact of co-formulated drugs on the thermoresponsive behaviours, are known. Furthermore, it has not been demonstrated that the materials are compatible with devices to generate sprays of the correct profiles for nasal administration. In this study we investigate the potential of thermoresponsive BCS-stabilised emulsions for the nasal delivery of licensed molecular therapeutics to examine the potential of BCS emulsion systems as a carrier for medicines. It was found that thermoresponsive behaviours can be maintained in the presence of drug substances, and that the liberation of the incorporated drugs occurs in a sustained manner. The BCS appear to have comparable cytotoxicity to common excipients and significantly enhanced retention on nasal tissue compared to even well-established mucoadhesives. The emulsions were incorporated into a spray device to demonstrate that the materials can be atomised with a plume appropriate for nasal administration prior to in situ gelation
Self-assembly of toll-like receptor (TLR2/6) agonist lipidated amino acid or peptide conjugates: distinct morphologies and bioactivities
Get PDFToll-like receptor (TLR) agonists are of interest in immunotherapy and cancer vaccines. The most common agonists of TLR2 are based on Pam2Cys or Pam3Cys. In the former, two palmitoyl (Pam) fatty acids are linked to a glycerylcysteine motif by ester linkages. Pam3Cys is analogous but contains an extra Pam group on the α-amine. Here, we compare the self-assembly in aqueous solution of the parent Pam2CysOH and Pam3Cys amino acid conjugates to that of Pam2CysSK4 and Pam3CysSK4 which are potent TLR2 agonists bearing the CysSK4 peptide sequence. All four conjugates exhibit a critical aggregation concentration above which self-assembled structures are formed. We find through a combination of small-angle X-ray scattering (SAXS), cryogenic transmission electron microscopy (cryo-TEM), and confocal fluorescence microscopy remarkable differences in self-assembled nanostructures. Pam2CysOH and Pam3CysOH both form unilamellar vesicles, although these are larger for the latter compound, an effect ascribed to enhanced membrane rigidity. This is in contrast to previously reported morphologies for Pam2CysSK4 and Pam3CysSK4, which are spherical micelles or predominantly wormlike micelles, respectively [Hamley, I. W.; et al. Toll-like Receptor Agonist Lipopeptides Self-Assemble into Distinct Nanostructures. Chem. Comm. 2014, 50, 15948-15951]. We also examine the effect of introduction in the bulky N-terminal Fmoc [fluorenylmethoxycarbonyl] group on the self-assembly of Fmoc-Pam2CysOH. This compound also forms vesicles (above a critical aggregation concentration, determined from dye probe fluorescence experiments) in aqueous solution, larger than those for Pam2CysOH and with a population of perforated/compound vesicles. The carboxyl-coated (and amino-coated for Pam2CysOH) vesicles demonstrated here represent a promising system for future development toward bionanotechnology applications such as immune therapies. Conjugates Pam2CysOH, Pam2CysSK4, and Pam3CysSK4 show good cytocompatibility at low concentrations, and in fact, the cell compatibility extends over a wider concentration range for Pam2CysOH. The TLR2/6 agonist activity was assessed using an assay that probes secreted alkaline phosphatase (SEAP) in NF-κB-SEAP reporter HEK293 cells expressing human TLR2 and TLR6, and Pam2CySOH shows significant activity, although not to the extent of Pam2CysSK4 or Pam3CysSK4. Thus, Pam2CysOH in particular is of interest as a vesicle-forming TLR2/6 agonist and stimulator of immune response
Multivariate optimization of mechanically ventilated photovoltaic double-skin façade system for the cold conditions of composite climate zone
Get PDFAssessing the performance of a multi-storey building equipped with a mechanically
ventilated photovoltaic-double skin façade (photovoltaic-DSF) system during cold weather
conditions is crucial. This is because the demand for heating in buildings rises as outdoor
temperatures decrease. This study formulates and verifies mathematical models to evaluate the
energy performance of a building integrated with a mechanically ventilated photovoltaicdouble skin façade (photovoltaic-DSF) system in Jaipur’s cold climate, which is part of India’s
composite climate zone. The system was installed and observed during the winter months
(December to February). The experimental design utilised a Taguchi L25 orthogonal array,
considering variables such as air cavity thickness, air velocity, and photovoltaic (PV) panel
transparency. Based on experimental findings, multiple linear regression analysis was used to
predict three key performance metrics: The solar heat gain coefficient (SHGC), photovoltaic
panel electrical output, and indoor daylight illuminance, all as influenced by the design
parameters. The analysis of variance (ANOVA) confirmed the statistical significance of these
relationships, and the model demonstrated a strong correlation with field measurements (R
2 >
0.90), validating the accuracy of the developed mathematical correlations. The analysis reveals
that a photovoltaic DSF system integrated into a multi-storey building, featuring a photovoltaic
panel with 50% transparency, an air velocity of 5 m/s, and a 50 mm air cavity, achieves
maximum energy performance under cold climate conditions in a composite climate. These
insights can help in designing energy-efficient photovoltaic-DSF systems specifically
optimised for winter conditions in composite climate zones
Dominant drivers of Jupiter's H3+ Northern Aurora: 1. magnetic field strength and planetary local time
Get PDFJupiter's auroral regions are marked by considerable spatial and temporal variability, with numerous sources of auroral enhancements, making it difficult to isolate individual causes of emission brightness. Here, we utilize a data set of 13,000 near-infrared
images of Jupiter mapped into latitude, longitude and planetary local time to separate out various sources of emission brightening, smoothed over hundreds of hours of integration and tens of days of observing. We show that
equatorial emission is well correlated to planetary local time, indicating that equatorial ionospheric emission is dominated by solar Extreme Ultraviolet (EUV) ionization on the dayside of the planet.
main auroral emission is strongly anti-correlated with surface magnetic field strength (with a Pearson correlation of −0.90), and is also strongly correlated with planetary local time (changing in brightness in the same way as equatorial emission with a Pearson correlation of 0.93). This is the first time such strong correlations have been shown at Jupiter, and may be the first evidence of such direct correlations at any planet, including Earth. Both of these correlations are thought to ultimately result from changes in ionospheric electrical conductivity driven by changing magnetic field strength and solar EUV ionization. This suggests the
aurora is significantly controlled by breakdown in co-rotation currents flowing deep into the ionosphere, and that this deep layer contains an important component of solar ionization. However, polar auroral emission does not correlate well with planetary local time, suggesting much more complex processes drive the varying emission within this region
Investigating the relationship between gut microbiota and electrocortical signatures of feedback processing: an ERP study
Get PDFRationale Evaluative processing of action outcome is considered crucial for learning and adaptive adjustments of behaviour. Feedback-related negativity (FRN) is an event-related potential elicited by feedback presentation, with implicated neural sources in the anterior cingulate cortex. Bidirectional communications within the brain-gut-microbiota axis modulate cognition and behaviour, and microbial composition has been associated with medial prefrontal cortex function and clinical risk for depression.
Objectives The present study aimed to investigate associations between specific gut microbiota and the FRN.
Methods Twenty-nine healthy participants completed self-report measures of depression and a Faces and Feedback task
during electroencephalography recording. Select implicated microbiota genera were enumerated from stool samples (Clos-
tridium, Lactobacillus), along with plasma C-reactive protein (CRP) as an index of systemic inflammation.
Results FRN amplitude for positive feedback was positively correlated with microbiota abundance. The relationship between Clostridium and FRN was confirmed by multilevel modelling analysis, controlling for depression and CRP. The latter was positively associated with FRN amplitude.
Conclusions Findings suggest that the brain-gut-microbiota-axis may modulate or be modulated by self-monitoring pro-
cesses. The current work provides insights into neurophysiological mechanisms underlying reward processing and indicates novel directions for therapeutic interventions, such as those that modulate the gut microbiome
A genotype-guided nutritional intervention to reduce cardiometabolic risk factors in young adults: study protocol for a randomized controlled trial
No full textBackground & Aims
Cardiometabolic diseases (CMD), including cardiovascular disease, obesity and diabetes, are major public health challenges influenced by lifestyle factors (e.g., diet), vitamin D status, and genetic predisposition. Single nucleotide polymorphisms (SNPs) contribute to genetic risk scores for CMD-related traits (M-GRS) and recent research suggests that genotype-based nutritional interventions have the potential to reduce these risks. This study aims to evaluate the effectiveness of genotype-guided nutritional interventions versus standard dietary recommendations in young adults.
Methods
This 12-month study includes a 6-month intervention phase and a 6-month free-living phase. Data will be collected at baseline, 3, 6 and 12 months. We plan to recruit young adults (aged 23-29) previously genotyped from the Obesity, Lifestyle, and Diabetes in Brazil (BOLD) study and randomized by BMI, sex, and M-GRS based on 34 SNPs. The control group will follow a standard Brazilian diet with CMD-related recommendations and 1000 IU of vitamin D3 daily. The personalized intervention group will receive a genotype-guided dietary plan based on gene-diet interactions for SNPs in the M-GRS, along with personalized vitamin D3 supplementation (1000 or 4000 IU) based on their genetic risk for deficiency (D-GRS). Body composition, biochemical markers and metabolomics will be assessed, with the reduction in body fat percentage as the primary outcome.
Discussion
This study will contribute to precision nutrition by assessing genotype-guided dietary recommendations for CMD risk management, potentially demonstrating how genetic information can optimize dietary interventions and reduce CMD burdens, improving overall health outcomes
Typical perceptual sensitivity to changes in interpersonal distance in developmental prosopagnosia
Get PDFSocial perception research has traditionally sought to elucidate the visual processing engaged by the faces and bodies of individuals. Recently, however, there has been growing interest in how we perceive dyadic interactions between people. Early findings suggest that dyads arranged face-to-face may engage neurocognitive processing similar to that recruited by faces. Given these parallels, we sought to determine whether developmental prosopagnosics (DPs), who exhibit lifelong face recognition difficulties, also exhibit impaired perception of facing dyads. The focus of our investigation was interpersonal distance – a key visual feature of dyadic social interactions. Participants completed three distance change detection tasks. Two of the tasks depicted distance changes during dyadic social interactions (fighting and dancing). A third task depicted distance changes using non-social objects (a pair of grandfather clocks). If DP is associated with impoverished perception of dyadic interactions, we reasoned that DPs should exhibit diminished sensitivity to distance changes
on the Dancers Task and the Boxers Task, but not on the Clocks Task. Contrary to this prediction, however, DPs and typical controls did not differ significantly in their ability to detect distance changes on any of the tasks. Although the visual processing of faces and facing dyads exhibit certain similarities, these findings suggest that the underlying perceptual mechanisms may dissociate
Are all farmers technically inefficient? Evidence from smallholder rice producers in Ghana
No full textThis study applied the zero-inefficiency stochastic frontier (ZISF) to analyse the technical efficiency of 333 improved rice-farming households for the 2012/2013 farming season in Ghana. The ZISF accommodates fully efficient rice farms alongside technically inefficient farms under a common
production technology. The results revealed that 39% of rice farms were fully technically efficient, with zero inefficiency within a common production frontier. The mean technical efficiency estimate amongst the inefficient farms was 67.8%, implying that these rice farms could increase their output by 32% without changing the levels of inputs used, if they improved their efficiency and operated on
the production frontier. There were increasing returns to scale (1.65), with farm size, seed, labour and fertiliser having a positive effect on rice output. Similarly, controlling rice field water levels through levelling and bunding, and weeding the rice field at least two times during the production season, increased technical efficiency. The study recommends cultivation of improved rice varieties, fertiliser application, expanding acreage and easing labour constraints to increase rice output,
together with weeding and managing plot water levels to improve efficiency in rice production. Specifically, Ghana’s ‘Planting for Food and Jobs’ programme should expand access to improved rice varieties, fertiliser use, agricultural mechanisation services and other labour-saving technologies to enhance rice output. In addition, the agricultural extension service should be well-resourced to disseminate best practices in rice cultivation to farmers
The impact of projected extinctions on avian functional diversity
No full textSince the Late Pleistocene at least 610 birds have gone extinct, including 165 since
1500 CE. Extinctions on this scale vastly exceed those seen in the fossil record, and
erode ecosystem processes, threatening ecosystem stability and resilience. Amid
ongoing species loss, we have limited understanding of how projected extinctions will
affect the diversity of species morphology, referred to as functional diversity. Functional
diversity is underrepresented in conservation efforts, even though it often responds
differently to human activity than traditional measures of biodiversity such as species
richness. Large-scale studies of functional diversity were previously limited by data
availability, but the release of a near-complete trait database for birds, and the
development of methods which can handle large quantities of continuous, multivariate
data provides an opportunity to assess functional diversity change at a scale not before
possible. In this thesis I quantify the impact of projected extinctions on avian functional
diversity and propose new approaches for tracking functional diversity change, to
support the preservation of biodiversity in its entirety. To do this I,
1) show that current data and methods are sufficient to estimate functional
diversity at large scales across many taxa;
2) demonstrate that both species richness and functional richness are threatened
by human activity, and additional conservation measures will be needed to
protect functional diversity;
3) develop a metric to track progress in the conservation of functional diversity
from local to global scales.
My findings support the need to monitor functional diversity alongside species richness
and show that conservation strategies which focus on species richness are inadequate
to conserve functional diversity in its entirety. Future work should integrate functional
diversity and ecosystem functioning research across scales to fully harness trait-based
approaches for understanding the consequences of global change