Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia. Resistance is characterized by prolonged in vivo parasite clearance times (PCTs) following artesunate treatment. ...The biological basis is unclear. The hypothesis that delayed parasite clearance results from a stage-specific reduction in artemisinin sensitivity of the circulating young asexual parasite ring stages was examined. A mathematical model was developed, describing the intrahost parasite stage-specific pharmacokinetic-pharmacodynamic relationships. Model parameters were estimated using detailed pharmacokinetic and parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from Pailin (western Cambodia) where artemisinin resistance was evident and 40 patients from Wang Pha (northwestern Thailand) where efficacy was preserved. The mathematical model reproduced the observed parasite clearance for each patient with an accurate goodness of fit (rmsd: 0.03-0.67 in log₁₀ scale). The parameter sets that provided the best fits with the observed in vivo data consist of a highly conserved concentration-effect relationship for the trophozoite and schizont parasite stages, but a variable relationship for the ring stages. The model-derived assessment suggests that the efficacy of artesunate on ring stage parasites is reduced significantly in Pailin. This result supports the hypothesis that artemisinin resistance mainly reflects reduced ring-stage susceptibility and predicts that doubling the frequency of dosing will accelerate clearance of artemisinin-resistant parasites.
The Spallation Neutron Source accelerator system design Alonso, J.; Arenius, D.; Bergmann, B. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
11/2014, Letnik:
763
Journal Article
Recenzirano
The Spallation Neutron Source (SNS) was designed and constructed by a collaboration of six U.S. Department of Energy national laboratories. The SNS accelerator system consists of a 1GeV linear ...accelerator and an accumulator ring providing 1.4MW of proton beam power in microsecond-long beam pulses to a liquid mercury target for neutron production. The accelerator complex consists of a front-end negative hydrogen-ion injector system, an 87MeV drift tube linear accelerator, a 186MeV side-coupled linear accelerator, a 1GeV superconducting linear accelerator, a 248-m circumference accumulator ring and associated beam transport lines. The accelerator complex is supported by ~100 high-power RF power systems, a 2K cryogenic plant, ~400 DC and pulsed power supply systems, ~400 beam diagnostic devices and a distributed control system handling ~100,000 I/O signals. The beam dynamics design of the SNS accelerator is presented, as is the engineering design of the major accelerator subsystems.
Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n = 14,539), moderate (n = 2077), and high (n = 2083) levels of malaria ...transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/µL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24.
Summary
Objective To assess the prevalence of counterfeit antimalarial drugs in Southeast (SE) Asia.
Design Cross‐sectional survey.
Setting Pharmacies and shops selling antimalarial drugs in ...Myanmar (Burma), Lao PDR, Vietnam, Cambodia and Thailand.
Main outcome measures Proportion of artemisinin derivatives or mefloquine containing drugs of substandard quality.
Results Of the 188 tablet packs purchased which were labelled as ‘artesunate’ 53% did not contain any artesunate. All counterfeit artesunate tablets were labelled as manufactured by ‘Guilin Pharma’, and refinements of the fake blisterpacks made them often hard to distinguish from their genuine counterparts. No other artemisinin derivatives were found to be counterfeited. Of the 44 mefloquine samples, 9% contained <10% of the expected amount of active ingredient.
Conclusions An alarmingly high proportion of antimalarial drugs bought in pharmacies and shops in mainland SE Asia are counterfeit, and the problem has increased significantly compared with our previous survey in 1999–2000. This is a serious threat to public health in the region.
Human haploinsufficiency of the transcription factor Tcf4 leads to a rare autism spectrum disorder called Pitt-Hopkins syndrome (PTHS), which is associated with severe language impairment and ...development delay. Here, we demonstrate that Tcf4 haploinsufficient mice have deficits in social interaction, ultrasonic vocalization, prepulse inhibition, and spatial and associative learning and memory. Despite learning deficits, Tcf4(+/−) mice have enhanced long-term potentiation in the CA1 area of the hippocampus. In translationally oriented studies, we found that small-molecule HDAC inhibitors normalized hippocampal LTP and memory recall. A comprehensive set of next-generation sequencing experiments of hippocampal mRNA and methylated DNA isolated from Tcf4-deficient and WT mice before or shortly after experiential learning, with or without administration of vorinostat, identified “memory-associated” genes modulated by HDAC inhibition and dysregulated by Tcf4 haploinsufficiency. Finally, we observed that Hdac2 isoform-selective knockdown was sufficient to rescue memory deficits in Tcf4(+/−) mice.
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•A Tcf4(+/−) mouse model is reported for Pitt-Hopkins syndrome (PTHS)•HDAC inhibition rescues learning and memory deficits of PTHS mice•Hdac2 is a therapeutic target for cognitive enhancement•Genes with altered mRNA and CpG Me due to learning are dysregulated in PTHS
Kennedy et al. describe a mouse model for Pitt-Hopkins syndrome (PTHS), a rare intellectual disability caused by haploinsufficiency of the transcription factor Tcf4. RNA-seq and MBD-seq of hippocampal tissue reveal broad dysregulation in the transcription and DNA methylation of memory-related genes and identify Hdac2 inhibition as a potential therapy for Pitt-Hopkins syndrome.
A classification system is described that was developed for inland aquatic ecosystems in South Africa, including wetlands. The six-tiered classification system is based on a top-down, hierarchical ...classification of aquatic ecosystems, following the functionally-oriented hydrogeomorphic (HGM) approach to classification but incorporating structural attributes at the lower levels of the hierarchy. At Level 1, a distinction is made between inland, estuarine and shallow marine systems using the degree of connectivity to the open ocean as the key discriminator. Inland systems are characterised by the complete absence of marine exchange and/or tidal influence. At Level 2, inland systems are grouped according to the most appropriate spatial framework for the particular application. At Level 3, four primary Landscape Units are distinguished (Valley floor, Slope, Plain, Bench) on the basis of the topographic position within which a particular inland aquatic ecosystem is situated, in recognition of the influence that the landscape setting has over hydrological and hydrodynamic processes acting within an aquatic ecosystem. Level 4 identifies HGM Units, defined primarily according to landform, hydrological characteristics and hydrodynamics. The following primary HGM Units (or HGM Types), which represent the main units of analysis for the classification system, are distinguished at Level 4A: (1) River; (2) Floodplain Wetland; (3) Channelled Valley-Bottom Wetland; (4) Unchannelled Valley-Bottom Wetland; (5) Depression; (6) Seep; (7) Wetland Flat. Secondary discriminators are applied at Level 5 to classify the hydrological regime of an HGM Unit, and Descriptors at Level 6 to categorise a range of biophysical attributes. The HGM Unit at Level 4 and the Hydrological Regime at Level 5 together constitute a Functional Unit, which represents the focal point of the classification system. The utility of the classification system is ultimately dependent on the level to which ecosystem units are classified, which is in turn constrained by the type and extent of information available.
Hundreds of gas- and particle-phase organic acids were measured in a rural ponderosa pine forest in Colorado, USA, during BEACHON-RoMBAS (Bio-hydro-atmosphere interactions of Energy, Aerosols, ...Carbon, H2O, Organics & Nitrogen - Rocky Mountain Biogenic Aerosol Study). A recently developed micro-orifice volatilization impactor high-resolution time-of-flight chemical ionization mass spectrometer (MOVI-HRToF-CIMS) using acetate (CH3C(O)O-) as the reagent ion was used to selectively ionize and detect acids semicontinuously from 20 to 30 August 2011, with a measurement time resolution of ~1.5 h. At this site 98% of the organic acid mass is estimated to be in the gas phase, with only ~2% in the particle phase. We investigated gas-particle partitioning, quantified as the fraction in the particle phase (Fp), of C1-C18 alkanoic acids, six known terpenoic acids, and bulk organic acids vs. carbon number. Data were compared to the absorptive partitioning model and suggest that bulk organic acids at this site follow absorptive partitioning to the organic aerosol mass. The rapid response (<1-2 h) of partitioning to temperature changes for bulk acids suggests that kinetic limitations to equilibrium are minor, which is in contrast to conclusions of some recent laboratory and field studies, possibly due to lack of very low ambient relative humidities at this site. Time trends for partitioning of individual and groups of acids were mostly captured by the model, with varying degrees of absolute agreement. Species with predicted substantial fractions in both the gas and particle phases show better absolute agreement, while species with very low predicted fractions in one phase often show poor agreement, potentially due to thermal decomposition, inlet adsorption, or other issues. Partitioning to the aqueous phase is predicted to be smaller than to the organic phase for alkanoic and bulk acids, and has different trends with time and carbon number than observed experimentally. This is due to the limited additional functionalization observed for the bulk acids. Partitioning to water appears to only play a role for the most oxidized acids during periods of high aerosol liquid water. Based on measurement-model comparison we conclude that species carbon number and oxygen content, together with ambient temperature, control the volatility of organic acids and are good predictors for partitioning at this site. Partitioning of bulk acids is more consistent with model predictions for hydroxy acids, hydroperoxyacids, or polyacids, and less so for keto acids.
Fireflies and their luminous courtships have inspired centuries of scientific study. Today firefly luciferase is widely used in biotechnology, but the evolutionary origin of bioluminescence within ...beetles remains unclear. To shed light on this long-standing question, we sequenced the genomes of two firefly species that diverged over 100 million-years-ago: the North American
and Japanese
To compare bioluminescent origins, we also sequenced the genome of a related click beetle, the Caribbean
, with bioluminescent biochemistry near-identical to fireflies, but anatomically unique light organs, suggesting the intriguing hypothesis of parallel gains of bioluminescence. Our analyses support independent gains of bioluminescence in fireflies and click beetles, and provide new insights into the genes, chemical defenses, and symbionts that evolved alongside their luminous lifestyle.
More than three-quarters of the baryonic content of the Universe resides in a highly diffuse state that is difficult to detect, with only a small fraction directly observed in galaxies and galaxy ...clusters
. Censuses of the nearby Universe have used absorption line spectroscopy
to observe the 'invisible' baryons, but these measurements rely on large and uncertain corrections and are insensitive to most of the Universe's volume and probably most of its mass. In particular, quasar spectroscopy is sensitive either to the very small amounts of hydrogen that exist in the atomic state, or to highly ionized and enriched gas
in denser regions near galaxies
. Other techniques to observe these invisible baryons also have limitations; Sunyaev-Zel'dovich analyses
can provide evidence from gas within filamentary structures, and studies of X-ray emission are most sensitive to gas near galaxy clusters
. Here we report a measurement of the baryon content of the Universe using the dispersion of a sample of localized fast radio bursts; this technique determines the electron column density along each line of sight and accounts for every ionized baryon
. We augment the sample of reported arcsecond-localized
fast radio bursts with four new localizations in host galaxies that have measured redshifts of 0.291, 0.118, 0.378 and 0.522. This completes a sample sufficiently large to account for dispersion variations along the lines of sight and in the host-galaxy environments
, and we derive a cosmic baryon density of Formula: see text (95 per cent confidence; h
= H
/(70 km s
Mpc
) and H
is Hubble's constant). This independent measurement is consistent with values derived from the cosmic microwave background and from Big Bang nucleosynthesis
.
Dr Peter Henriksen (consultant cardiologist and honorary senior lecturer, Edinburgh Heart Centre, NHS Lothian, University Hospitals Division), Professor C P Day (Professor of Liver Medicine, ...Institute of Cellular Medicine, Newcastle University), Dr D Thorburn (consultant hepatologist, Liver Unit, Royal Free Hospital, London), Mr D F Mirza (consultant hepatobiliary and transplant surgeon, Liver Unit, University Hospital Birmingham NHS Foundation Trust), Dr J W Ferguson (consultant hepatologist and honorary senior lecturer, Liver Unit, University Hospital Birmingham NHS Foundation Trust), Dr G Auzinger (consultant intensive care medicine, Liver Intensive Therapy Unit, King's College Hospital London NHS Foundation Trust), Dr M Allison (consultant hepatologist, Liver Unit, Department of Medicine, Cambridge University Hospital NHS Foundation Trust), Dr J W Tomlinson (reader in endocrinology, Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham), H Manley (British Liver Trust), Dr K J Simpson (senior lecturer in hepatology, University of Edinburgh and honorary consultant physician, Scottish Liver Transplantation Unit, Royal Infirmary Edinburgh), Professor S G Hubscher (Leith Professor and Professor of Hepatic Pathology, University of Birmingham, and consultant histopathologist, University Hospital Birmingham NHS Foundation Trust), Dr C Millson (consultant hepatologist, St James's University Hospital, Leeds), Dr J Oben (Wellcome Trust senior lecturer and consultant hepatologist, University College London, Centre for Hepatology, Royal Free Hospital, London), Professor J M Neuberger (Associate Medical Director for Organ Donation and Transplantation, NHS Blood and Transplant and honorary consultant physician, Queen Elizabeth Hospital, Birmingham), Dr P J McKiernan (consultant paediatrician, Liver Unit, Birmingham Children's Hospital) and Dr J I Wyatt (consultant histopathologist, St James's University Hospital, Leeds). Criteria for diagnosis of NASH group should include an established clinical and histological diagnosis of NASH on liver biopsy, or a histological diagnosis of cryptogenic cirrhosis with a clinical phenotype compatible with underlying NASH, as defined by the presence of three or more components of the metabolic syndrome prior to liver transplant (LT).
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