Heating of nanoparticles (NPs) using an AC magnetic field depends on several factors, and optimization of these parameters can improve the efficiency of heat generation for effective cancer therapy ...while administering a low NP treatment dose. This study investigated magnetic field strength and frequency, NP size, NP concentration, and solution viscosity as important parameters that impact the heating efficiency of iron oxide NPs with magnetite (Fe3O4) and maghemite (γ-Fe2O3) crystal structures. Heating efficiencies were determined for each experimental setting, with specific absorption rates (SARs) ranging from 3.7 to 325.9W/g Fe. Magnetic heating was conducted on iron oxide NPs synthesized in our laboratories (with average core sizes of 8, 11, 13, and 18nm), as well as commercially-available iron oxides (with average core sizes of 8, 9, and 16nm). The experimental magnetic coil system made it possible to isolate the effect of magnetic field parameters and independently study the effect on heat generation. The highest SAR values were found for the 18nm synthesized particles and the maghemite nanopowder. Magnetic field strengths were applied in the range of 15.1–47.7kA/m, with field frequencies ranging from 123 to 430kHz. The best heating was observed for the highest field strengths and frequencies tested, with results following trends predicted by the Rosensweig equation. An increase in solution viscosity led to lower heating rates in nanoparticle solutions, which can have significant implications for the application of magnetic fluid hyperthermia in vivo.
•Heating was tested in seven iron oxide nanoparticles for different magnetic fields.•Confirms an optimal nanoparticle size for heating that agrees with the literature.•Verifies Rosenweig's equation to predict the effect of field frequency on heating.•Reports reduced heating in high viscosity environments.
Human zinc deficiency increases susceptibility to bacterial infection. Although zinc supplementation therapies can reduce the impact of disease, the molecular basis for protection remains unclear. ...Streptococcus pneumoniae is a major cause of bacterial pneumonia, which is prevalent in regions of zinc deficiency. We report that dietary zinc levels dictate the outcome of S. pneumoniae infection in a murine model. Dietary zinc restriction impacts murine tissue zinc levels with distribution post-infection altered, and S. pneumoniae virulence and infection enhanced. Although the activation and infiltration of murine phagocytic cells was not affected by zinc restriction, their efficacy of bacterial control was compromised. S. pneumoniae was shown to be highly sensitive to zinc intoxication, with this process impaired in zinc restricted mice and isolated phagocytic cells. Collectively, these data show how dietary zinc deficiency increases sensitivity to S. pneumoniae infection while revealing a role for zinc as a component of host antimicrobial defences.
During infection, the host sequesters essential nutrients, such as zinc, to combat invading microbes. Despite the ability of the immune effector protein calprotectin to bind zinc with subpicomolar ...affinity,
is able to successfully compete with the host for zinc. However, the zinc importers expressed by
remain unknown. Our investigations have revealed that
possesses two importers, AdcABC and CntABCDF, which are induced in response to zinc limitation. While AdcABC is similar to known zinc importers in other bacteria, CntABCDF has not previously been associated with zinc acquisition. Concurrent loss of the two systems severely impairs the ability of
to obtain zinc and grow in zinc-limited environments. Further investigations revealed that the Cnt system is responsible for the ability of
to compete with calprotectin for zinc in culture and contributes to acquisition of zinc during infection. The
locus also enables
to produce the broad-spectrum metallophore staphylopine. Similarly to the Cnt transporter, loss of staphylopine severely impairs the ability of
to resist host-imposed zinc starvation, both in culture and during infection. Further investigations revealed that together staphylopine and the Cnt importer function analogously to siderophore-based iron acquisition systems in order to facilitate zinc acquisition by
Analogous systems are found in a broad range of Gram-positive and Gram-negative bacterial pathogens, suggesting that this new type of zinc importer broadly contributes to the ability of bacteria to cause infection.
A critical host defense against infection is the restriction of zinc availability. Despite the subpicomolar affinity of the immune effector calprotectin for zinc,
can successfully compete for this essential metal. Here, we describe two zinc importers, AdcABC and CntABCDF, possessed by
, the latter of which has not previously been associated with zinc acquisition. The ability of
to compete with the host for zinc is dependent on CntABCDF and the metallophore staphylopine, both in culture and during infection. These results expand the mechanisms utilized by bacteria to obtain zinc, beyond Adc-like systems, and demonstrate that pathogens utilize strategies similar to siderophore-based iron acquisition to obtain other essential metals during infection. The staphylopine synthesis machinery is present in a diverse collection of bacteria, suggesting that this new family of zinc importers broadly contributes to the ability of numerous pathogens to cause infection.
Streptococcus pneumoniae is the primary cause of community-acquired bacterial pneumonia with rates of penicillin and multidrug-resistance exceeding 80% and 40%, respectively. The innate immune ...response generates a variety of antimicrobial agents to control infection, including zinc stress. Here, we characterize the impact of zinc intoxication on S. pneumoniae, observing disruptions in central carbon metabolism, lipid biogenesis, and peptidoglycan biosynthesis. Characterization of the pivotal peptidoglycan biosynthetic enzyme GlmU indicates a sensitivity to zinc inhibition. Disruption of the sole zinc efflux pathway, czcD, renders S. pneumoniae highly susceptible to β-lactam antibiotics. To dysregulate zinc homeostasis in the wild-type strain, we investigated the safe-for-human-use ionophore 5,7-dichloro-2-(dimethylamino)methylquinolin-8-ol (PBT2). PBT2 rendered wild-type S. pneumoniae strains sensitive to a range of antibiotics. Using an invasive ampicillin-resistant strain, we demonstrate in a murine pneumonia infection model the efficacy of PBT2 + ampicillin treatment. These findings present a therapeutic modality to break antibiotic resistance in multidrug-resistant S. pneumoniae.
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•Zinc can impair the activity of the peptidoglycan biosynthetic enzyme GlmU•The zinc ionophore PBT2 overwhelms S. pneumoniae zinc resistance mechanisms•PBT2-mediated zinc intoxication breaks resistance to multiple antibiotic classes•PBT2 rescues ampicillin efficacy during drug-resistant S. pneumoniae lung infection
Antibiotic resistance is a growing threat to treatment of pneumonia caused by Streptococcus pneumoniae. Brazel et al. show how zinc can be used to break bacterial antibiotic resistance. They repurpose the safe-for-human-use zinc transporting ionophore, 5,7-dichloro-2-(dimethylamino)methylquinolin-8-ol (PBT2), to break bacterial drug resistance during lung infection and restore the efficacy of ampicillin treatment.
Multidisciplinary heart failure (HF) programs reduce hospital readmission and improve clinical outcomes. Although dietitians are often members of such teams, no randomized studies have demonstrated ...the independent benefit of dietitian-administered dietary counseling for patients with HF. The purpose of this study was to evaluate the effect of dietitian education on adherence to a sodium-restricted diet in ambulatory patients with stable HF.
Patients with HF (left ventricular ejection fraction <35%) were randomized into a dietitian education group (n = 23) or a usual care group (n = 24), then observed for 3 months. Both groups received a 2 g/d dietary sodium prescription. The usual care group received nutrition advice by way of self-help literature, whereas the dietitian education group returned for 2 counseling sessions with a dietitian.
Dietitian education resulted in a significant decrease in sodium intake at 3 months (2.80 ± 0.30 to 2.14 ± 0.23 g/d,
P < .05). In contrast, there was no change in sodium intake in the usual care group (3.00 ± 0.31 to 2.74 ± 0.35 g/d,
P = ns).
Dietitian-administered counseling was more effective than providing literature in reducing dietary sodium intake in patients with stable HF.
Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ...ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.
We investigated the efficacy of insulin-pump therapy in insulin-dependent diabetics, aged 18 to 69 years, by comparing the metabolic control achieved in 100 patients using this technique with that ...previously obtained by conventional insulin therapy. Patients were followed during pump therapy for as long as 15 months. Fasting and nonfasting blood glucose levels (mean +/- S.E.M.) decreased from 201 +/- 6 and 213 +/- 6 mg per deciliter (11.2 +/- 0.3 and 11.8 +/- 0.3 mmol per liter), respectively, to 158 +/- 5 and 145 +/- 3 mg per deciliter (8.77 +/- 0.3 and 8.05 +/- 0.2 mmol per liter) after one month of pump therapy (P less than 0.001). Ninety-three patients had improved blood sugar control; 71 per cent had a mean blood sugar concentration of 150 mg per deciliter (8.3 mmol per liter) or less after six months. Glycosylated hemoglobin values became normal in 44 per cent of 88 patients who had follow-up determinations. In over 500 patient-months there were four episodes of ketoacidosis and five episodes of serious hypoglycemia. Three patients abandoned pump therapy. We conclude that insulin-pump therapy is acceptable to patients and that it can be successfully applied to clinical practice and large-scale research studies.
Carbon sequestration (CO2 disposal) may be only a temporary measure for bridging from the current situation in which carbon emissions to the atmosphere are unacceptably high and increasing, to a ...carbon-free economy, but it is a practical and immediate process that can be undertaken. Sequestration methods vary in effectiveness and cost, and each may have different opportunities, benefits, and drawbacks and periods of time over which the CO2 is retarded from emitting into the atmosphere. Sequestration methods need to be tested on an appropriate scale as quickly as possible because carbon sequestration may help reverse the trend of increasing carbon emissions and remediate the atmosphere for a significant period of time.
Among proposed carbon sequestration technologies, temporary storage of CO2 in the deep ocean may be the most practicable for many locations, and possibly the most energy efficient and cost-effective. In addition, an important added value benefit may be derived from deep ocean sequestration. A CO2 hydrate industrial crystallization desalination/disposal process is particularly applicable to oceanic islands and coastal areas adjacent to narrow continental shelves where abyssal depths can be reached by the dense, dissolved CO2-rich water gravity mass flows composed of processed water rejected from the desalination process.
Magnetic iron oxide nanoparticles (MNPs) have been developed for magnetic fluid hyperthermia (MFH) cancer therapy, where cancer cells are treated through the heat generated by application of a high ...frequency magnetic field. This heat has also been proposed as a mechanism to trigger release of chemotherapy agents. In each of these cases, MNPs with optimal heating performance can be used to maximize therapeutic effect while minimizing the required dosage of MNPs. In this study, the heating efficiencies (or specific absorption rate, SAR) of two types of MNPs were evaluated experimentally and then predicted from their magnetic properties. MNPs were also incorporated in the core of poly(ethylene glycol-b-caprolactone) micelles, co-localized with rhodamine B fluorescent dye attached to polycaprolactone to monitor local, nanoscale temperatures during magnetic heating. Despite a relatively high SAR produced by these MNPs, no significant temperature rise beyond that observed in the bulk solution was measured by fluorescence in the core of the magnetic micelles. MNPs were also incorporated into a macro-scale agarose gel system that mimicked a tumor targeted by MNPs and surrounded by healthy tissues. The agarose-based tumor models showed that targeted MNPs can reach hyperthermia temperatures inside a tumor with a sufficient MNP concentration, while causing minimal temperature rise in the healthy tissue surrounding the tumor.
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•Evaluated the use of magnetic iron oxide nanoparticles for cancer hyperthermia•Determined power generation in nanoparticles experimentally and theoretically•Elucidated local temperature in core of polymeric micelles during hyperthermia•Evaluated bulk temperature rise in cm sized tumors during magnetic hyperthermia•Compared the rise in bulk solution temperature to local nanoparticle temperature
ABSTRACT During infection, the host sequesters essential nutrients, such as zinc, to combat invading microbes. Despite the ability of the immune effector protein calprotectin to bind zinc with ...subpicomolar affinity, Staphylococcus aureus is able to successfully compete with the host for zinc. However, the zinc importers expressed by S. aureus remain unknown. Our investigations have revealed that S. aureus possesses two importers, AdcABC and CntABCDF, which are induced in response to zinc limitation. While AdcABC is similar to known zinc importers in other bacteria, CntABCDF has not previously been associated with zinc acquisition. Concurrent loss of the two systems severely impairs the ability of S. aureus to obtain zinc and grow in zinc-limited environments. Further investigations revealed that the Cnt system is responsible for the ability of S. aureus to compete with calprotectin for zinc in culture and contributes to acquisition of zinc during infection. The cnt locus also enables S. aureus to produce the broad-spectrum metallophore staphylopine. Similarly to the Cnt transporter, loss of staphylopine severely impairs the ability of S. aureus to resist host-imposed zinc starvation, both in culture and during infection. Further investigations revealed that together staphylopine and the Cnt importer function analogously to siderophore-based iron acquisition systems in order to facilitate zinc acquisition by S. aureus. Analogous systems are found in a broad range of Gram-positive and Gram-negative bacterial pathogens, suggesting that this new type of zinc importer broadly contributes to the ability of bacteria to cause infection. IMPORTANCE A critical host defense against infection is the restriction of zinc availability. Despite the subpicomolar affinity of the immune effector calprotectin for zinc, Staphylococcus aureus can successfully compete for this essential metal. Here, we describe two zinc importers, AdcABC and CntABCDF, possessed by S. aureus, the latter of which has not previously been associated with zinc acquisition. The ability of S. aureus to compete with the host for zinc is dependent on CntABCDF and the metallophore staphylopine, both in culture and during infection. These results expand the mechanisms utilized by bacteria to obtain zinc, beyond Adc-like systems, and demonstrate that pathogens utilize strategies similar to siderophore-based iron acquisition to obtain other essential metals during infection. The staphylopine synthesis machinery is present in a diverse collection of bacteria, suggesting that this new family of zinc importers broadly contributes to the ability of numerous pathogens to cause infection.
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