Chagas disease, caused by the protozoan parasite
, affects millions of people in the Americas and across the world, leading to considerable morbidity and mortality. Current treatment options, ...benznidazole (BNZ) and nifurtimox, offer limited efficacy and often lead to adverse side effects because of long treatment durations. Better treatment options are therefore urgently required. Here, we describe a pyrrolopyrimidine series, identified through phenotypic screening, that offers an opportunity to improve on current treatments. In vitro cell-based washout assays demonstrate that compounds in the series are incapable of killing all parasites; however, combining these pyrrolopyrimidines with a subefficacious dose of BNZ can clear all parasites in vitro after 5 days. These findings were replicated in a clinically predictive in vivo model of chronic Chagas disease, where 5 days of treatment with the combination was sufficient to prevent parasite relapse. Comprehensive mechanism of action studies, supported by ligand-structure modeling, show that compounds from this pyrrolopyrimidine series inhibit the Q
active site of
cytochrome b, part of the cytochrome bc
complex of the electron transport chain. Knowledge of the molecular target enabled a cascade of assays to be assembled to evaluate selectivity over the human cytochrome b homolog. As a result, a highly selective and efficacious lead compound was identified. The combination of our lead compound with BNZ rapidly clears
parasites, both in vitro and in vivo, and shows great potential to overcome key issues associated with currently available treatments.
With a remarkably higher theoretical energy density compared to lithium-ion batteries (LIBs) and abundance of elemental sulfur, lithium sulfur (Li–S) batteries have emerged as one of the most ...promising alternatives among all the post LIB technologies. In particular, the coupling of solid polymer electrolytes (SPEs) with the cell chemistry of Li–S batteries enables a safe and high-capacity electrochemical energy storage system, due to the better processability and less flammability of SPEs compared to liquid electrolytes. However, the practical deployment of all solid-state Li–S batteries (ASSLSBs) containing SPEs is largely hindered by the low accessibility of active materials and side reactions of soluble polysulfide species, resulting in a poor specific capacity and cyclability. In the present work, an ultrahigh performance of ASSLSBs is obtained via an anomalous synergistic effect between (fluorosulfonyl)(trifluoromethanesulfonyl)imide anions inherited from the design of lithium salts in SPEs and the polysulfide species formed during the cycling. The corresponding Li–S cells deliver high specific/areal capacity (1394 mAh gsulfur –1, 1.2 mAh cm–2), good Coulombic efficiency, and superior rate capability (∼800 mAh gsulfur –1 after 60 cycles). These results imply the importance of the molecular structure of lithium salts in ASSLSBs and pave a way for future development of safe and cost-effective Li–S batteries.
Currently, in developed countries, nights are excessively illuminated (light at night), whereas daytime is mainly spent indoors, and thus people are exposed to much lower light intensities than under ...natural conditions. In spite of the positive impact of artificial light, we pay a price for the easy access to light during the night: disorganization of our circadian system or chronodisruption (CD), including perturbations in melatonin rhythm. Epidemiological studies show that CD is associated with an increased incidence of diabetes, obesity, heart disease, cognitive and affective impairment, premature aging and some types of cancer. Knowledge of retinal photoreceptors and the discovery of melanopsin in some ganglion cells demonstrate that light intensity, timing and spectrum must be considered to keep the biological clock properly entrained. Importantly, not all wavelengths of light are equally chronodisrupting. Blue light, which is particularly beneficial during the daytime, seems to be more disruptive at night, and induces the strongest melatonin inhibition. Nocturnal blue light exposure is currently increasing, due to the proliferation of energy-efficient lighting (LEDs) and electronic devices. Thus, the development of lighting systems that preserve the melatonin rhythm could reduce the health risks induced by chronodisruption. This review addresses the state of the art regarding the crosstalk between light and the circadian system.
Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages—erythrocytic, gametocyte, liver, and gamete activation stages—indicating that selective Pf20S ...inhibitors possess the potential to be therapeutic, prophylactic, and transmission‐blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time‐dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin‐sensitive and artemisinin‐resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum‐infected mice.
Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission‐blocking antimalarials. We present a novel and highly species‐selective malaria proteasome inhibitor that potently reduced parasitemia in humanized mice infected with P. falciparum, the deadliest plasmodium parasite.
Rechargeable batteries are becoming increasingly important for our daily life due to their strong capability of efficiently storing electric energy under chemical form. The replacement of ...conventional liquid electrolytes with polymer electrolytes (PEs) has been deemed as one of the most viable solutions towards safer and higher energy density electrochemical energy storage systems which are coveted for e-mobility applications (e.g., electric vehicles, EVs). In recent years, the introduction of inorganic materials into PEs has captured escalating interest, aiming at harmonizing advantages from both organic and inorganic phases. In this review, we present the progress and recent advances in PEs containing nano-sized inorganic materials, with due attention paid to the role of inorganic phases on the physical and chemical properties of the electrolytes. The paradigm shift from composite polymer electrolytes (CPEs, obtained by physical blending) to hybrid polymer electrolytes (HPEs, obtained by chemical grafting) is highlighted and the possible improvement and future directions in CPEs and HPEs are discussed.
Current treatments against chronic hepatitis B (CHB) include pegylated interferon alpha (Peg‐IFNα) and nucleos(t)ide analogs (NAs), the latter targeting the viral retrotranscriptase, thus inhibiting ...de novo viral production. Although these therapies control infection and improve the patient's quality of life, they do not cure HBV‐infected hepatocytes. A complete HBV cure is currently not possible because of the presence of the stable DNA intermediate covalently closed circular DNA (cccDNA). Current efforts are focused on achieving a functional cure, defined by the loss of Hepatitis B surface antigen (HBsAg) and undetectable HBV DNA levels in serum, and on exploring novel targets and molecules that are in the pipeline for early clinical trials. The likelihood of achieving a long‐lasting functional cure, with no rebound after therapy cessation, is higher using combination therapies targeting different steps in the hepatitis B virus (HBV) replication cycle. Novel treatments and their combinations are discussed for their potential to cure HBV infection, as well as exciting new technologies that could directly target cccDNA and cure without killing the infected cells.
Non-invasive ventilation (NIV) is an effective form of treatment in patients with obesity hypoventilation syndrome (OHS) who have concomitant severe obstructive sleep apnoea (OSA). However, there is ...a paucity of evidence on the efficacy of NIV in patients with OHS without severe OSA. We performed a multicentre randomised clinical trial to determine the comparative efficacy of NIV versus lifestyle modification (control group) using daytime arterial carbon dioxide tension (PaCO2) as the main outcome measure.
Between May 2009 and December 2014 we sequentially screened patients with OHS without severe OSA. Participants were randomised to NIV versus lifestyle modification and were followed for 2 months. Arterial blood gas parameters, clinical symptoms, health-related quality of life assessments, polysomnography, spirometry, 6-min walk distance test, blood pressure measurements and healthcare resource utilisation were evaluated. Statistical analysis was performed using intention-to-treat analysis.
A total of 365 patients were screened of whom 58 were excluded. Severe OSA was present in 221 and the remaining 86 patients without severe OSA were randomised. NIV led to a significantly larger improvement in PaCO2 of -6 (95% CI -7.7 to -4.2) mm Hg versus -2.8 (95% CI -4.3 to -1.3) mm Hg, (p<0.001) and serum bicarbonate of -3.4 (95% CI -4.5 to -2.3) versus -1 (95% CI -1.7 to -0.2 95% CI) mmol/L (p<0.001). PaCO2 change adjusted for NIV compliance did not further improve the inter-group statistical significance. Sleepiness, some health-related quality of life assessments and polysomnographic parameters improved significantly more with NIV than with lifestyle modification. Additionally, there was a tendency towards lower healthcare resource utilisation in the NIV group.
NIV is more effective than lifestyle modification in improving daytime PaCO2, sleepiness and polysomnographic parameters. Long-term prospective studies are necessary to determine whether NIV reduces healthcare resource utilisation, cardiovascular events and mortality.
NCT01405976; results.
Chickens were used to investigate plasma disposition of florfenicol after single intravenous (i.v.) and oral dose (20 mg kg−1 body weight) and to study residue depletion of florfenicol and its major ...metabolite florfenicol-amine after multiple oral doses (40 mg kg−1 body weight, daily for 3 days). Plasma and tissue samples were analyzed using a high-performance liquid chromatography (HPLC) method. After i.v. and oral administration, plasma concentration−time curves were best described by a two-compartment open model. The mean ±standard deviation (SD) elimination half-life (t 1/2β) of florfenicol in plasma was 7.90 ± 0.48 and 8.34 ± 0.64 h after i.v. and oral administration, respectively. The maximum plasma concentration was 10.23 ± 1.67 μg mL−1, and the interval from oral administration until maximal concentration was 0.63 ± 0.07 h. Oral bioavailability was found to be 87 ± 16%. Florfenicol was converted to florfenicol-amine. After multiple oral dose (40 mg kg−1 body weight, daily for 3 days), in kidney and liver, concentrations of florfenicol (119.34 ± 31.81 and 817.34 ± 91.65 μg kg−1, respectively) and florfenicol-amine (60.67 ± 13.05 and 48.50 ± 13.07 μg kg−1, respectively) persisted for 7 days. The prolonged presence of residues of florfenicol and florfenicol-amine in edible tissues can play an important role in human food safety, because the compounds could give rise to a possible health risk. A withdrawal time of 6 days was necessary to ensure that the residues of florfenicol were less than the maximal residue limits or tolerance established by the European Union.
Suppressing the mobility of anionic species in polymer electrolytes (PEs) is essential for mitigating the concentration gradient and internal cell polarization, and thereby improving the stability ...and cycle life of rechargeable alkali metal batteries. Now, an ether‐functionalized anion (EFA) is used as a counter‐charge in a lithium salt. As the salt component in PEs, it achieves low anionic diffusivity but sufficient Li‐ion conductivity. The ethylene oxide unit in EFA endows nanosized self‐agglomeration of anions and trapping interactions between the anions and its structurally homologous matrix, poly(ethylene oxide), thus suppressing the mobility of negative charges. In contrast to previous strategies of using anion traps or tethering anions to a polymer/inorganic backbone, this work offers a facile and elegant methodology on accessing selective and efficient Li‐ion transport in PEs and related electrolyte materials (for example, composites and hybrid electrolytes).
The right counter‐charge: An ether‐functionalized anion (EFA) as counter‐charge to a lithium ion could achieve low anionic diffusivity but sufficient Li‐ion conductivity in a polymer electrolyte. This feature is highly desired in high‐performance solid‐state lithium batteries.
Fumonisins (FBs) are widespread Fusarium toxins commonly found as corn contaminants. FBs could cause a variety of diseases in animals and humans, such as hepatotoxic, nephrotoxic, hepatocarcinogenic ...and cytotoxic effects in mammals. To date, almost no review has addressed the toxicity of FBs in relation to oxidative stress and their metabolism. The focus of this article is primarily intended to summarize the progress in research associated with oxidative stress as a plausible mechanism for FB-induced toxicity as well as the metabolism. The present review showed that studies have been carried out over the last three decades to elucidate the production of reactive oxygen species (ROS) and oxidative stress as a result of FBs treatment and have correlated them with various types of FBs toxicity, indicating that oxidative stress plays critical roles in the toxicity of FBs. The major metabolic pathways of FBs are hydrolysis, acylation and transamination. Ceramide synthase, carboxylesterase FumD and aminotransferase FumI could degrade FB
1
and FB
2
. The cecal microbiota of pigs and alkaline processing such as nixtamalization can also transform FB
1
into metabolites. Most of the metabolites of FB
1
were less toxic than FB
1
, except its partial (pHFB
1
) metabolites. Further understanding of the role of oxidative stress in FB-induced toxicity will throw new light on the use of antioxidants, scavengers of ROS, as well as on the blind spots of metabolism and the metabolizing enzymes of FBs. The present review might contribute to reveal the toxicity of FBs and help to protect against their oxidative damage.
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