Objectives
The objective of the present study was to shed some light on pharmacokinetics of cyclodextrins (CDs) and drugs after oral and parenteral administration of inclusion complexes.
Key findings
...The complex binding constant in water can predict pharmacokinetics after parenteral administration, but it has to be considered in the context of the physiological environment, where plasma proteins compete with CDs for drug binding. Neither drug/CD nor drug/protein complexes can extravasate, but differently from proteins, CDs are readily cleared through glomerular filtration. In such intricate interrelationships, for complexes with low‐to‐mid binding constant, binding of drug to plasma proteins will mainly dictate the pharmacokinetics. Oppositely, for drugs showing large CD complex binding constant and low protein binding, significant decrease in distribution volume and enhanced excretion of unmetabolized drug are observed; thus, relevant changes in bioavailability can be predicted. In the case of oral administration, volume for dilution/dissolution of the complexes is relatively low and hence excess CD can hamper drug absorption from the gastrointestinal (GI) tract.
Summary
CDs are well‐established multipurpose excipients for overcoming organoleptic and biopharmaceutical deficiencies of a variety of drugs. Balances between free and complexed drug in the GI tract and between drug–CD binding and drug–protein binding in plasma seem to play a relevant role in drug pharmacokinetics.
A study was conducted to (a) determine if beef cattle hair contains cortisol at measurable concentrations, and (b) identify the effect of hair location and collection method on hair cortisol ...concentrations. Hair samples (0.5g) from the head, neck, shoulder, hip, and switch were collected from twelve Angus cross bulls (313.1±14.7kg BW) using two sampling methods: plucking, to ensure collection of the hair follicles; and clipping, using an electric razor to ensure collection of the hair as close as possible to the skin. After two washings with isopropanol, hair samples were ground with a ball mill for 5min at 22Hz, sonicated with methanol for 30min, and incubated on a shaker for 18h, at 50°C and 100rpm. The supernatant was pipetted off and evaporated in a block heater, at 45°C under a stream of nitrogen. Samples were reconstituted with phosphate buffered saline before quantification of cortisol with a competitive immunoassay. The described method was successful in detecting cortisol in all the hair samples, with concentrations ranging from 0.30 to 5.31pg/mg. The intra-assay coefficient of variation (CV) ranged from 3.6% to 6.0%, while the inter-assay CV ranged from 5.4% to 11.2%. The cortisol concentration was greater (P<0.05) in the hair from the tail (1.99±0.189pg/mg) compared with the head and the shoulder (1.14 and 0.82±0.189pg/mg, respectively), and in the hair from the neck and the hip (1.50 and 1.59±0.189pg/mg, respectively) compared with the shoulder (0.82±0.189pg/mg). Cortisol concentration was greater (P<0.01) in hair samples collected by clipping (2.35±0.176pg/mg) than by plucking (1.75±0.176pg/mg). There was a day×location interaction (P=0.01), where the hair from the head, neck and shoulder had a lower cortisol concentration at d 28 than at d 1 of the experiment. Data show a significant positive association between cortisol concentration in saliva samples and its level in hair from the hip (r=0.52) and the tail (r=0.63). There was also a trend for a positive association between fecal glucocorticoid metabolites and cortisol concentration in the hair from the neck and the tail (r=0.46 and 0.47, respectively). Results indicate that hair can be used as matrix to measure cortisol levels in beef cattle. Clipping hair from the tail seems to be the most suitable way for measuring cortisol concentration in hair.
Hydrophilic nanogels combine the advantages of hydrogels with certain advantages that are inherent in their nanoscale size. Similar to macrogels, nanogels can contain and protect drugs and regulate ...their release by incorporating high-affinity functional groups, stimuli-responsive conformations and biodegradable bonds into the polymer network. Similar to nanoparticles, nanogels can easily be administered in liquid form for parenteral drug delivery. The nanoscale size of nanogels gives them a high specific surface area that is available for further bioconjugation of active targeting agents. Biodistribution and drug release can be modulated through size adjustments. The incorporation of hydrophilic cyclodextrin (CD) moieties into the polymeric network of the nanogels provides them with a drug loading and release mechanism that is based on the formation of inclusion complexes without decreasing the hydrophilicity of the network. The covalent attachment of CD molecules to the chemically crosslinked networks may enable the CDs to display fully their ability to form complexes, while simultaneously preventing drug release upon media dilution. The preparation, characterization and advantages for pharmaceutical and biomedical applications of CD-based nanogels are reviewed in this article.
In recent decades, the fire regime of the Mediterranean Basin has been disturbed by various factors: climate change; forest management policies; land cover; changed landscape. Size and severity have ...notably increased, which in turn have increased large fires events with >500ha burned (high severity). In spite of Mediterranean ecosystems' high resilience to fire, these changes have implied more vulnerability and reduced natural recovery with irreparable long-term negative effects. Knowledge of the response of ecosystems to increasing severity, mainly in semiarid areas, is still lacking, which is needed to rehabilitate and restore burned areas.
Our approach assessed the resilience concept by focusing on the recovery of ecosystem functions and services, measured as changes in the composition and diversity of plant community vegetation and structure. This will be validated in the long term as a model of ecosystem response. Also, depending on the pre-fire characteristics of vegetation, fire severity and the post-fire management, this approach will lead to tools that can be applied to implement post-fire restoration efforts in order to help decision making in planning activities.
Regarding Mediterranean ecosystems' ability to recover after wildfires, this study concludes that pre-fire communities are resilient in these fire-prone areas, but the window for natural recovery in semiarid areas of Aleppo pine forest in SE Iberian Peninsula varied from 3 to 15 post-fire years. Fire severity was also key for effects on the ecosystem: the vegetation types of areas burned with low and medium severity recovered naturally, while those areas with a high-severity burn induced shrublands. We concluded that very strong regeneration activity exists in the short term, and that the negative effects of medium- and high-severity fire are evidenced in the mid and long term, which affect natural recovery. Adaptive forest management to rehabilitate and restore burned Mediterranean ecosystems should be implemented.
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•We assessed resilience of Aleppo pine forests in Eastern Mediterranean Basin•Recovery of ecosystem was monitored in short, medium and long-term after wildfires.•Natural recovery was found in areas burned with low and medium severity.•Areas burned with high severity of fire changed to shrublands.•Fire severity influenced the recovery time of Aleppo pine forest.
Forest fires-affected landscapes enhance sudden runoff discharges, high sediment loads and extreme soil erosion rates. Different soil stabilisation treatments, such as mulching, can be applied to ...avoid runoff and soil erosion after wildfires. To characterise the post-fire soil erosion rates and runoff generation, we selected a Mediterranean forest affected by a wildfire in Lietor (Spain) to determine the sediment yield (dry sediment (DS), total suspended sediment (TSS), total dissolved sediment (TDS)) and runoff discharge in twelve 200 m2 (10 × 20 m) plots. Immediately after the wildfire, six plots were covered by straw and six other plots were set up as controls. Three months after the wildfire, logging activities were performed and the experimental designs were as follows: mulching + logging (three replicates), non-mulching + logging (three replicates), non-mulching + non-logging (three replicates) and mulching + non-logging (three replicates). During the period after wildfire and before salvage logging, the straw mulch controlled the soil erosion rates (DS, TSS and TDS) versus the non-mulched plots, but straw had no real impact on runoff discharge. For the period after salvage logging, once again runoff did not differ when comparing all the treatments. DS was higher in the non-mulched and non-logging plots, whereas the highest TSS was found in the non-mulched plots (in logged or non-logged plots). TDS was higher in the mulched and non-logged plots. We conclude that straw mulch is efficient management in recent fire-affected mountainous terrains to control soil loss immediately after wildfire. Moreover, logging operations done 3 months after wildfire did not necessary generate higher DS, TSS, TDS rates, mainly because of the type of machinery used for forest operations.
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•Runoff was not influenced by mulching either in logged or not logged plots.•Mulching is an efficient post-fire practice for controlling soil erosion.•Logging operations did not necessary generates higher rates of soil erosion.•The type of machinery used for forest operations influences soil erosion.
The nematode Caenorhabditis briggsae has been used as a model in comparative genomics studies with Caenorhabditis elegans because of their striking morphological and behavioral similarities. However, ...the potential of C. briggsae for comparative studies is limited by the quality of its genome resources. The genome resources for the C. briggsae laboratory strain AF16 have not been developed to the same extent as C. elegans. The recent publication of a new chromosome-level reference genome for QX1410, a C. briggsae wild strain closely related to AF16, has provided the first step to bridge the gap between C. elegans and C. briggsae genome resources. Currently, the QX1410 gene models consist of software-derived gene predictions that contain numerous errors in their structure and coding sequences. In this study, a team of researchers manually inspected over 21,000 gene models and underlying transcriptomic data to repair software-derived errors. We designed a detailed workflow to train a team of nine students to manually curate gene models using RNA read alignments. We manually inspected the gene models, proposed corrections to the coding sequences of over 8,000 genes, and modeled thousands of putative isoforms and untranslated regions. We exploited the conservation of protein sequence length between C. briggsae and C. elegans to quantify the improvement in protein-coding gene model quality and showed that manual curation led to substantial improvements in the protein sequence length accuracy of QX1410 genes. Additionally, collinear alignment analysis between the QX1410 and AF16 genomes revealed over 1,800 genes affected by spurious duplications and inversions in the AF16 genome that are now resolved in the QX1410 genome. Community-based, manual curation using transcriptome data is an effective approach to improve the quality of software-derived protein-coding genes. The detailed protocols provided in this work can be useful for future large-scale manual curation projects in other species. Our manual curation efforts have brought the QX1410 gene models to a comparable level of quality as the extensively curated AF16 gene models. The improved genome resources for C. briggsae provide reliable tools for the study of Caenorhabditis biology and other related nematodes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aim: Mediterranean terrestrial ecosystems serve as reference laboratories for the investigation of global change because of their transitional climate, the high spatiotemporal variability of their ...environmental conditions, a rich and unique biodiversity and a wide range of socio-economic conditions. As scientific development and environmental pressures increase, it is increasingly necessary to evaluate recent progress and to challenge research priorities in the face of global change. Location: Mediterranean terrestrial ecosystems. Methods: This article revisits the research priorities proposed in a 1998 assessment. Results: A new set of research priorities is proposed: (1) to establish the role of the landscape mosaic on fire-spread; (2) to further research the combined effect of different drivers on pest expansion; (3) to address the interaction between drivers of global change and recent forest management practices; (4) to obtain more realistic information on the impacts of global change and ecosystem services; (5) to assess forest mortality events associated with climatic extremes; (6) to focus global change research on identifying and managing vulnerable areas; (7) to use the functional traits concept to study resilience after disturbance; (8) to study the relationship between genotypic and phenotypic diversity as a source of forest resilience; (9) to understand the balance between storage and water resources; (10) to analyse the interplay between landscape-scale processes and biodiversity conservation; (11) to refine models by including interactions between drivers and socio-economic contexts; (12) to understand forest-atmosphere feedbacks; (13) to represent key mechanisms linking plant hydraulics with landscape hydrology. Main conclusions: (1) The interactive nature of different global change drivers remains poorly understood. (2) There is a critical need for the rapid development of regional-and global-scale models that are more tightly connected with largescale experiments, data networks and management practice. (3) More attention should be directed to drought-related forest decline and the current relevance of historical land use.
Subacute ruminal acidosis (SARA) is a common digestive disorder in cattle fed high concentrate diets, and it is generally defined as a reduction in ruminal pH below 6.0 that results in lower fibre ...digestion, changes in rumen fermentation profile, irregular intake and reduced performance. However, the true cause of the observed effects in the rumen is unclear. Feeding high concentrate diets rich in non-structural carbohydrates and low in fibre results in a reduction in ruminal pH and the development of SARA. These two events (higher concentrate and low pH) occur at the same time and, therefore, are confounded. The question is if the effects reported are due to the reduction of pH or to the type of diet fed. The answer to this question is not only academic, because if the effects are pH dependent, then the terminology acidosis and the use of buffers and alkalizers are justified. However, if the effects are due to the type of diet, then buffers would have a limited effect and we should be looking at different types of solutions and terminology. Few experiments have addressed that objective, but the limited evidence available indicates that the effects typically attributed to SARA are due to a combination of pH and type of diet fermented. Although buffers and alkalizers help in the control of SARA, alternative strategies dealing with the control of the fermentation pathways should be investigated. Streptococcus bovis is considered the main lactic acid producer in the rumen and develops efficiently at relatively low pH. Megasphaera elsdenii and Selenomonas ruminantium are major lactic acid utilizers. Strategies to reduce lactic acid producers and (or) increase lactic acid utilizers may be helpful in the control of SARA in a way different from pH control. Feeding M. elsdenii to beef cattle reduced rumen lactic acid concentration and increased pH. Yeast and malic acid stimulate lactic acid uptake by S. ruminantium. Also, vaccination or oral supplementation of polyclonal antibodies against S. bovis reduced bacterial counts and lactic acid concentration, and increased ruminal pH. Evidence suggests that SARA is not only a pH-dependent pathology, but it is also the result of changes in the microbial population secondary to the type of diet fed. Therefore, we propose to re-name SARA as a “high-concentrate syndrome”, and suggest that a combination of pH modulating strategies and microbial population control are required to attempt to reduce its consequences.
Short-term fire-induced changes to the soil microbial community are usually closely associated to fire severity, which essentially consists in the fire-induced loss or decomposition of organic matter ...above ground and below ground. Many functional processes and soil properties, including plant recolonization and soil microorganism activity, depend on fire severity. Seven days after burning, we evaluated the impact of two fire severities (low and high) on basic soil properties and the microbial communities in an outdoor experimental controlled system composed of six forest soil monoliths. The magnitude of change in microbial community was far greater than the change in physical and chemical soil properties. Total N was the only selected soil property that significantly varied depending on fire severity. The severely burned soils experienced significant changes in overall microbial biomass composition and phylogenetic composition of bacterial communities in comparison with control plots. Immediately after the fire, in fact, phyla and genera such as Acidobacteria-Gp4 or Bacteroidetes-Ohtaekwangia were much more abundant in the control monoliths. On the other hand, Firmicutes or Proteobacteria (e.g. Firmicutes Paenibacillus, Proteobacteria Phenylobacterium) were relatively more abundant in the monoliths burned with high severity in comparison with the low severity burned ones. Overall, the effect of fire on soil microbial communities was greater in the high severity burned monoliths than in the low severity burned ones. We concluded that in Mediterranean forest ecosystems, fire significantly alters soil bacterial composition depending on its severity.
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•Fire significantly alters soil bacterial composition depending on severity.•The fire impact was more marked in the high than in low severity burned soils.•Total N were the only soil property affected by fire.•The mesocosm scale is optimal to validate results taken from field recordings.
Albendazole (a benzimidazole) and ivermectin (a macrocyclic lactone) are the two most commonly co-administered anthelmintic drugs in mass-drug administration programs worldwide. Despite emerging ...resistance, we do not fully understand the mechanisms of resistance to these drugs nor the consequences of delivering them in combination. Albendazole resistance has primarily been attributed to variation in the drug target, a beta-tubulin gene. Ivermectin targets glutamate-gated chloride channels (GluCls), but it is unknown whether GluCl genes are involved in ivermectin resistance in nature. Using Caenorhabditis elegans, we defined the fitness costs associated with loss of the drug target genes singly or in combinations of the genes that encode GluCl subunits. We quantified the loss-of-function effects on three traits: (i) multi-generational competitive fitness, (ii) fecundity, and (iii) development. In competitive fitness and development assays, we found that a deletion of the beta-tubulin gene ben-1 conferred albendazole resistance, but ivermectin resistance required the loss of two GluCl genes (avr-14 and avr-15). The fecundity assays revealed that loss of ben-1 did not provide any fitness benefit in albendazole conditions and that no GluCl deletion mutants were resistant to ivermectin. Next, we searched for evidence of multi-drug resistance across the three traits. Loss of ben-1 did not confer resistance to ivermectin, nor did loss of any single GluCl subunit or combination confer resistance to albendazole. Finally, we assessed the development of 124 C. elegans wild strains across six benzimidazoles and seven macrocyclic lactones to identify evidence of multi-drug resistance between the two drug classes and found a strong phenotypic correlation within a drug class but not across drug classes. Because each gene affects various aspects of nematode physiology, these results suggest that it is necessary to assess multiple fitness traits to evaluate how each gene contributes to anthelmintic resistance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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