196 research outputs found
A cognitive behavioural coaching intervention for the treatment of perfectionism and self-handicapping in a nonclinical population
Retargeting azithromycin analogues to have dual-modality antimalarial activity
Background: Resistance to front-line antimalarials (artemisinin combination therapies) is spreading, and development of new drug treatment strategies to rapidly kill Plasmodium spp. malaria parasites is urgently needed. Azithromycin is a clinically used macrolide antibiotic proposed as a partner drug for combination therapy in malaria, which has also been tested as monotherapy. However, its slow-killing 'delayed-death' activity against the parasite's apicoplast organelle and suboptimal activity as monotherapy limit its application as a potential malaria treatment. Here, we explore a panel of azithromycin analogues and demonstrate that chemical modifications can be used to greatly improve the speed and potency of antimalarial action. Results: Investigation of 84 azithromycin analogues revealed nanomolar quick-killing potency directed against the very earliest stage of parasite development within red blood cells. Indeed, the best analogue exhibited 1600-fold higher potency than azithromycin with less than 48 hrs treatment in vitro. Analogues were effective against zoonotic Plasmodium knowlesi malaria parasites and against both multi-drug and artemisinin-resistant Plasmodium falciparum lines. Metabolomic profiles of azithromycin analogue-treated parasites suggested activity in the parasite food vacuole and mitochondria were disrupted. Moreover, unlike the food vacuole-targeting drug chloroquine, azithromycin and analogues were active across blood-stage development, including merozoite invasion, suggesting that these macrolides have a multi-factorial mechanism of quick-killing activity. The positioning of functional groups added to azithromycin and its quick-killing analogues altered their activity against bacterial-like ribosomes but had minimal change on 'quick-killing' activity. Apicoplast minus parasites remained susceptible to both azithromycin and its analogues, further demonstrating that quick-killing is independent of apicoplast-targeting, delayed-death activity. Conclusion: We show that azithromycin and analogues can rapidly kill malaria parasite asexual blood stages via a fast action mechanism. Development of azithromycin and analogues as antimalarials offers the possibility of targeting parasites through both a quick-killing and delayed-death mechanism of action in a single, multifactorial chemotype.Amy L. Burns, Brad E. Sleebs, Ghizal Siddiqui, Amanda E. De Paoli, Dovile Anderson, Benjamin Liffner, Richard Harvey, James G. Beeson, Darren J. Creek, Christopher D. Goodman, Geoffrey I. McFadden, and Danny W. Wilso
Origin and Evolution of Saturn's Ring System
The origin and long-term evolution of Saturn's rings is still an unsolved
problem in modern planetary science. In this chapter we review the current
state of our knowledge on this long-standing question for the main rings (A,
Cassini Division, B, C), the F Ring, and the diffuse rings (E and G). During
the Voyager era, models of evolutionary processes affecting the rings on long
time scales (erosion, viscous spreading, accretion, ballistic transport, etc.)
had suggested that Saturn's rings are not older than 100 My. In addition,
Saturn's large system of diffuse rings has been thought to be the result of
material loss from one or more of Saturn's satellites. In the Cassini era, high
spatial and spectral resolution data have allowed progress to be made on some
of these questions. Discoveries such as the ''propellers'' in the A ring, the
shape of ring-embedded moonlets, the clumps in the F Ring, and Enceladus' plume
provide new constraints on evolutionary processes in Saturn's rings. At the
same time, advances in numerical simulations over the last 20 years have opened
the way to realistic models of the rings's fine scale structure, and progress
in our understanding of the formation of the Solar System provides a
better-defined historical context in which to understand ring formation. All
these elements have important implications for the origin and long-term
evolution of Saturn's rings. They strengthen the idea that Saturn's rings are
very dynamical and rapidly evolving, while new arguments suggest that the rings
could be older than previously believed, provided that they are regularly
renewed. Key evolutionary processes, timescales and possible scenarios for the
rings's origin are reviewed in the light of tComment: Chapter 17 of the book ''Saturn After Cassini-Huygens'' Saturn from
Cassini-Huygens, Dougherty, M.K.; Esposito, L.W.; Krimigis, S.M. (Ed.) (2009)
537-57
Influence of fast interstellar gas flow on dynamics of dust grains
The orbital evolution of a dust particle under the action of a fast
interstellar gas flow is investigated. The secular time derivatives of
Keplerian orbital elements and the radial, transversal, and normal components
of the gas flow velocity vector at the pericentre of the particle's orbit are
derived. The secular time derivatives of the semi-major axis, eccentricity, and
of the radial, transversal, and normal components of the gas flow velocity
vector at the pericentre of the particle's orbit constitute a system of
equations that determines the evolution of the particle's orbit in space with
respect to the gas flow velocity vector. This system of differential equations
can be easily solved analytically. From the solution of the system we found the
evolution of the Keplerian orbital elements in the special case when the
orbital elements are determined with respect to a plane perpendicular to the
gas flow velocity vector. Transformation of the Keplerian orbital elements
determined for this special case into orbital elements determined with respect
to an arbitrary oriented plane is presented. The orbital elements of the dust
particle change periodically with a constant oscillation period or remain
constant. Planar, perpendicular and stationary solutions are discussed.
The applicability of this solution in the Solar system is also investigated.
We consider icy particles with radii from 1 to 10 micrometers. The presented
solution is valid for these particles in orbits with semi-major axes from 200
to 3000 AU and eccentricities smaller than 0.8, approximately. The oscillation
periods for these orbits range from 10^5 to 2 x 10^6 years, approximately.Comment: 22 pages, 3 figures; Accepted for publication in Celestial Mechanics
and Dynamical Astronom
Targeting malaria parasites with novel derivatives of azithromycin
Introduction: The spread of artemisinin resistant Plasmodium falciparum parasites is of global concern and highlights the need to identify new antimalarials for future treatments. Azithromycin, a macrolide antibiotic used clinically against malaria, kills parasites via two mechanisms: ‘delayed death’ by inhibiting the bacterium-like ribosomes of the apicoplast, and ‘quick-killing’ that kills rapidly across the entire blood stage development. Methods: Here, 22 azithromycin analogues were explored for delayed death and quick-killing activities against P. falciparum (the most virulent human malaria) and P. knowlesi (a monkey parasite that frequently infects humans). Results: Seventeen analogues showed improved quick-killing against both Plasmodium species, with up to 38 to 20-fold higher potency over azithromycin after less than 48 or 28 hours of treatment for P. falciparum and P. knowlesi, respectively. Quick-killing analogues maintained activity throughout the blood stage lifecycle, including ring stages of P. falciparum parasites (5-fold more selective against P. falciparum than human cells. Isopentenyl pyrophosphate supplemented parasites that lacked an apicoplast were equally sensitive to quick-killing analogues, confirming that the quick killing activity of these drugs was not directed at the apicoplast. Further, activity against the related apicoplast containing parasite Toxoplasma gondii and the gram-positive bacterium Streptococcus pneumoniae did not show improvement over azithromycin, highlighting the specific improvement in antimalarial quick-killing activity. Metabolomic profiling of parasites subjected to the most potent compound showed a build-up of non-haemoglobin derived peptides that was similar to chloroquine, while also exhibiting accumulation of haemoglobin-derived peptides that was absent for chloroquine treatment. Discussion: The azithromycin analogues characterised in this study expand the structural diversity over previously reported quick-killing compounds and provide new starting points to develop azithromycin analogues with quickkilling antimalarial activity.Amy L. Burns, Brad E. Sleebs, Maria Gancheva, Kimberley T. McLean, Ghizal Siddiqui, Henrietta Venter, James G. Beeson, Ryan O, Handley, Darren J. Creek, Shutao Ma, Sonja Frölich, Christopher D. Goodman, Geoffrey I. McFadden, and Danny W. Wilso
Tidal Evolution of Close Binary Asteroid Systems
We provide a generalized discussion of tidal evolution to arbitrary order in
the expansion of the gravitational potential between two spherical bodies of
any mass ratio. To accurately reproduce the tidal evolution of a system at
separations less than five times the radius of the larger primary component,
the tidal potential due to the presence of a smaller secondary component is
expanded in terms of Legendre polynomials to arbitrary order rather than
truncated at leading order as is typically done in studies of well-separated
system like the Earth and Moon. The equations of tidal evolution including
tidal torques, the changes in spin rates of the components, and the change in
semimajor axis (orbital separation) are then derived for binary asteroid
systems with circular and equatorial mutual orbits. Accounting for higher-order
terms in the tidal potential serves to speed up the tidal evolution of the
system leading to underestimates in the time rates of change of the spin rates,
semimajor axis, and mean motion in the mutual orbit if such corrections are
ignored. Special attention is given to the effect of close orbits on the
calculation of material properties of the components, in terms of the rigidity
and tidal dissipation function, based on the tidal evolution of the system. It
is found that accurate determinations of the physical parameters of the system,
e.g., densities, sizes, and current separation, are typically more important
than accounting for higher-order terms in the potential when calculating
material properties. In the scope of the long-term tidal evolution of the
semimajor axis and the component spin rates, correcting for close orbits is a
small effect, but for an instantaneous rate of change in spin rate, semimajor
axis, or mean motion, the close-orbit correction can be on the order of tens of
percent.Comment: 40 pages, 2 tables, 8 figure
A resonant-term-based model including a nascent disk, precession, and oblateness: application to GJ 876
Investigations of two resonant planets orbiting a star or two resonant
satellites orbiting a planet often rely on a few resonant and secular terms in
order to obtain a representative quantitative description of the system's
dynamical evolution. We present a semianalytic model which traces the orbital
evolution of any two resonant bodies in a first- through fourth-order
eccentricity or inclination-based resonance dominated by the resonant and
secular arguments of the user's choosing. By considering the variation of
libration width with different orbital parameters, we identify regions of phase
space which give rise to different resonant ''depths,'' and propose methods to
model libration profiles. We apply the model to the GJ 876 extrasolar planetary
system, quantify the relative importance of the relevant resonant and secular
contributions, and thereby assess the goodness of the common approximation of
representing the system by just the presumably dominant terms. We highlight the
danger in using ''order'' as the metric for accuracy in the orbital solution by
revealing the unnatural libration centers produced by the second-order, but not
first-order, solution, and by demonstrating that the true orbital solution lies
somewhere ''in-between'' the third- and fourth-order solutions. We also present
formulas used to incorporate perturbations from central-body oblateness and
precession, and a protoplanetary or protosatellite thin disk with gaps, into a
resonant system. We quantify these contributions to the GJ 876 system, and
thereby highlight the conditions which must exist for multi-planet exosystems
to be significantly influenced by such factors. We find that massive enough
disks may convert resonant libration into circulation; such disk-induced
signatures may provide constraints for future studies of exoplanet systems.Comment: 39 pages of body text, 21 figures, 5 tables, 1 appendix, accepted for
publication in Celestial Mechanics and Dynamical Astronom
Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume
The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes
Acceptance and commitment therapy for people living with motor neuron disease: an uncontrolled feasibility study
Background
Motor neuron disease (MND) is a fatal, progressive neurodegenerative disease that causes progressive weakening and wasting of limb, bulbar, thoracic and abdominal muscles. Clear evidence-based guidance on how psychological distress should be managed in people living with MND (plwMND) is lacking. Acceptance and Commitment Therapy (ACT) is a form of psychological therapy that may be particularly suitable for this population. However, to the authors' knowledge, no study to date has evaluated ACT for plwMND. Consequently, the primary aim of this uncontrolled feasibility study was to examine the feasibility and acceptability of ACT for improving the psychological health of plwMND.
Methods
PlwMND aged ≥ 18 years were recruited from 10 UK MND Care Centres/Clinics. Participants received up to 8 one-to-one ACT sessions, developed specifically for plwMND, plus usual care. Co-primary feasibility and acceptability outcomes were uptake (≥ 80% of the target sample [N = 28] recruited) and initial engagement with the intervention (≥ 70% completing ≥ 2 sessions). Secondary outcomes included measures of quality of life, anxiety, depression, disease-related functioning, health status and psychological flexibility in plwMND and quality of life and burden in caregivers. Outcomes were assessed at baseline and 6 months.
Results
Both a priori indicators of success were met: 29 plwMND (104%) were recruited and 76% (22/29) attended ≥ 2 sessions. Attrition at 6-months was higher than anticipated (8/29, 28%), but only two dropouts were due to lack of acceptability of the intervention. Acceptability was further supported by good satisfaction with therapy and session attendance. Data were possibly suggestive of small improvements in anxiety and psychological quality of life from baseline to 6 months in plwMND, despite a small but expected deterioration in disease-related functioning and health status.
Conclusions
There was good evidence of acceptability and feasibility. Limitations included the lack of a control group and small sample size, which complicate interpretation of findings. A fully powered RCT to evaluate the clinical and cost-effectiveness of ACT for plwMND is underway
Measurements of differential production cross sections for a Z boson in association with jets in pp collisions at root s=8 TeV
Peer reviewe
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