Little is known about the side effects of micafungin in extremely low birth weight infants. In a retrospective single-center study, 19 extremely low birth weight infants were analyzed for micafungin ...efficacy and safety. At a mean±standard deviation daily dosage of 7.5 ± 2.0 mg/kg, no clinically relevant side effects were observed. A significant increase of liver enzymes was reversible after treatment.
The building blocks of life - nucleotides, amino acids and saccharides - give rise to a large variety of components and make up the hierarchical structures found in Nature. Driven by chirality and ...non-covalent interactions, helical and highly organised structures are formed and the way in which they fold correlates with specific recognition and hence function. A great amount of effort is being put into mimicking these highly specialised biosystems as biomaterials for biomedical applications, ranging from drug discovery to regenerative medicine. However, as well as lacking the complexity found in Nature, their bio-activity is sometimes low and hierarchical ordering is missing or underdeveloped. Moreover, small differences in folding in natural biomolecules (
, caused by mutations) can have a catastrophic effect on the function they perform. In order to develop biomaterials that are more efficient in interacting with biomolecules, such as proteins, DNA and cells, we speculate that incorporating order and handedness into biomaterial design is necessary. In this review, we first focus on order and handedness found in Nature in peptides, nucleotides and saccharides, followed by selected examples of synthetic biomimetic systems based on these components that aim to capture some aspects of these ordered features. Computational simulations are very helpful in predicting atomic orientation and molecular organisation, and can provide invaluable information on how to further improve on biomaterial designs. In the last part of the review, a critical perspective is provided along with considerations that can be implemented in next-generation biomaterial designs.
Aims/hypothesis
The study investigated cross-sectional associations of total amount and patterns of sedentary behaviour with glucose metabolism status and the metabolic syndrome.
Methods
We included ...2,497 participants (mean age 60.0 ± 8.1 years, 52% men) from The Maastricht Study who were asked to wear an activPAL accelerometer 24 h/day for 8 consecutive days. We calculated the daily amount of sedentary time, daily number of sedentary breaks and prolonged sedentary bouts (≥30 min), and the average duration of the sedentary bouts. To determine glucose metabolism status, participants underwent an oral glucose tolerance test. Associations of sedentary behaviour variables with glucose metabolism status and the metabolic syndrome were examined using multinomial logistic regression analyses.
Results
Overall, 1,395 (55.9%) participants had normal glucose metabolism, 388 (15.5%) had impaired glucose metabolism and 714 (28.6%) had type 2 diabetes. The odds ratio per additional hour of sedentary time was 1.22 (95% CI 1.13, 1.32) for type 2 diabetes and 1.39 (1.27, 1.53) for the metabolic syndrome. No significant or only weak associations were seen for the number of sedentary breaks, number of prolonged sedentary bouts or average bout duration with either glucose metabolism status or the metabolic syndrome.
Conclusions/interpretation
An extra hour of sedentary time was associated with a 22% increased odds for type 2 diabetes and a 39% increased odds for the metabolic syndrome. The pattern in which sedentary time was accumulated was weakly associated with the presence of the metabolic syndrome. These results suggest that sedentary behaviour may play a significant role in the development and prevention of type 2 diabetes, although longitudinal studies are needed to confirm our findings.
The detailed mechanisms by which the transferrin receptor (TfR) and associated ligands traffic across brain capillary endothelial cells (BECs) of the CNS-protective blood-brain barrier constitute an ...important knowledge gap within maintenance and regulation of brain iron homeostasis. This knowledge gap also presents a major obstacle in research aiming to develop strategies for efficient receptor-mediated drug delivery to the brain. While TfR-mediated trafficking from blood to brain have been widely studied, investigation of TfR-mediated trafficking from brain to blood has been limited. In this study we investigated TfR distribution on the apical and basal plasma membranes of BECs using expansion microscopy, enabling sufficient resolution to separate the cellular plasma membranes of these morphological flat cells, and verifying both apical and basal TfR membrane domain localization. Using immunofluorescence-based transcellular transport studies, we delineated endosomal sorting of TfR endocytosed from the apical and basal membrane, respectively, as well as bi-directional TfR transcellular transport capability. The findings indicate different intracellular sorting mechanisms of TfR, depending on the apicobasal trafficking direction across the BBB, with the highest transcytosis capacity in the brain-to-blood direction. These results are of high importance for the current understanding of brain iron homeostasis. Also, the high level of TfR trafficking from the basal to apical membrane of BECs potentially explains the low transcytosis which are observed for the TfR-targeted therapeutics to the brain parenchyma.
Chronic kidney disease, which is defined as having a reduced kidney function (estimated glomerular filtration rate (eGFR)) and/or signs of kidney damage (albuminuria), is highly prevalent in Western ...society and is associated with adverse health outcomes, such as cardiovascular disease. This warrants a search for risk factors of lower eGFR and higher albuminuria. Physical activity and sedentary behavior may be such risk factors.
To examine associations of physical activity (total, high, low), sedentary time and sedentary behavior patterns (breaks, prolonged bouts, average bout duration) with eGFR and albuminuria.
We examined these associations in 2,258 participants of the Maastricht Study (average age 60.1±8.1 years; 51.3% men), who wore an accelerometer 24h/day on 7 consecutive days. Associations with continuous eGFR and categories of urinary albumin excretion (UAE; <15 reference category, 15-<30, ≥30 mg/24h) were evaluated with linear regression analyses and multinomial logistic regression analyses, respectively.
After adjustment for potential confounders, each extra hour of total physical activity was associated with a more favorable kidney function (betaeGFR = 2.30 (95%CI = 1.46; 3.14)), whereas each extra hour of sedentary behavior was associated with a more adverse kidney function (betaeGFR = -0.71 (-1.08; -0.35)). Also, compared to individuals with the lowest levels of total physical activity, individuals with the highest levels had less kidney damage (OR15-<30mg/24h = 0.63 (0.41; 0.96), OR≥30mg/24h = 0.84 (0.53; 1.35). An extra hour of sedentary behavior was associated with more kidney damage (OR15-<30 mg/24h = 1.11 (1.01; 1.22), OR≥30 mg/24h = 1.10 (0.99; 1.22)). Further, a highly sedentary pattern was associated with a more adverse kidney function, but no association was seen with kidney damage.
Physical activity and sedentary behavior were associated with kidney function and kidney damage. Additionally, sedentary behavior patterns were associated with kidney function. Causal studies are required to examine whether this indeed implicates that prevention strategies should focus not only on increasing physical activity, but on reducing sedentary behavior as well.
An ab initio simulation scheme is introduced as a theoretical prescreening approach to facilitate and enhance the research for pH-sensitive biomarkers. The proton 1H and carbon 13C nuclear magnetic ...resonance (NMR) chemical shifts of the recently published marker for extracellular pH, 1,5–13C2zymonic acid (ZA), and the as yet unpublished (Z)-4-methyl-2-oxopent-3-enedioic acid (OMPD) were calculated with ab initio methods as a function of the pH. The influence of the aqueous solvent was taken into account either by an implicit solvent model or by explicit water molecules, where the latter improved the accuracy of the calculated chemical shifts considerably. The theoretically predicted chemical shifts allowed for a reliable NMR peak assignment. The pK a value of the first deprotonation of ZA and OMPD was simulated successfully whereas the parametrization of the implicit solvent model does not allow for an accurate description of the second pK a. The theoretical models reproduce the pH-induced chemical shift changes and the first pK a with sufficient accuracy to establish the ab initio prescreening approach as a valuable support to guide the experimental search for pH-sensitive biomarkers.
Covid-19 in Brazil: A sad scenario Marinho, Pedro Rafael D.; Cordeiro, Gauss M.; Coelho, Hemílio F.C. ...
Cytokine & growth factor reviews,
04/2021, Letnik:
58
Journal Article
Recenzirano
Odprti dostop
•The COVID-19 pandemic in Brazil has grown rapidly since February, 25.•The lethality rate for COVID-19 in Brazil is greater than those in other countries of Latin America.•An updated web application ...has been used by some health managers to guide COVID-19 public policies.
The main contribution of this article is to report general statistics about COVID-19 in Brazil, based on analysis of accumulated series of confirmed cases, deaths and lethality rates, in addition to presenting graphs of moving averages for states and municipalities. The data show that the pandemic in Brazil has grown rapidly since February 25th (date of the first reported case). Furthermore, the lethality rate of COVID-19 in Brazil is greater than in many other Latin American countries (Chile, Argentina, Uruguay and Paraguay). However, the number of new confirmed cases in Brazil has little statistical relevance because only a small part of the population has been tested. In relation to Brazilian municipalities, we highlight the 10 states with the highest lethality rates, ranked from highest to lowest. Also, predictions about the increaseor decrease innew cases and deaths for states and capital cities are presented. These results can help managers and researchers to better guide their decisions regarding COVID-19.
Brain endothelial cell-based in vitro models are among the most versatile tools in blood-brain barrier research for testing drug penetration to the central nervous system. Transcytosis of large ...pharmaceuticals across the brain capillary endothelium involves the complex endo-lysosomal system. This system consists of several types of vesicle, such as early, late and recycling endosomes, retromer-positive structures, and lysosomes. Since the endo-lysosomal system in endothelial cell lines of in vitro blood-brain barrier models has not been investigated in detail, our aim was to characterize this system in different models.
For the investigation, we have chosen two widely-used models for in vitro drug transport studies: the bEnd.3 mouse and the hCMEC/D3 human brain endothelial cell line. We compared the structures and attributes of their endo-lysosomal system to that of primary porcine brain endothelial cells.
We detected significant differences in the vesicular network regarding number, morphology, subcellular distribution and lysosomal activity. The retromer-positive vesicles of the primary cells were distinct in many ways from those of the cell lines. However, the cell lines showed higher lysosomal degradation activity than the primary cells. Additionally, the hCMEC/D3 possessed a strikingly unique ratio of recycling endosomes to late endosomes.
Taken together our data identify differences in the trafficking network of brain endothelial cells, essentially mapping the endo-lysosomal system of in vitro blood-brain barrier models. This knowledge is valuable for planning the optimal route across the blood-brain barrier and advancing drug delivery to the brain.
Abstract Bioethanol is a sustainable energy alternative and can contribute to global greenhouse-gas emission reductions by over 60%. Its industrial production faces various bottlenecks, including ...sub-optimal efficiency resulting from bacteria. Broad-spectrum removal of these contaminants results in negligible gains, suggesting that the process is shaped by ecological interactions within the microbial community. Here, we survey the microbiome across all process steps at two biorefineries, over three timepoints in a production season. Leveraging shotgun metagenomics and cultivation-based approaches, we identify beneficial bacteria and find improved outcome when yeast-to-bacteria ratios increase during fermentation. We provide a microbial gene catalogue which reveals bacteria-specific pathways associated with performance. We also show that Limosilactobacillus fermentum overgrowth lowers production, with one strain reducing yield by ~5% in laboratory fermentations, potentially due to its metabolite profile. Temperature is found to be a major driver for strain-level dynamics. Improved microbial management strategies could unlock environmental and economic gains in this US $ 60 billion industry enabling its wider adoption.
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