The cellular mechanism(s) linking macrophages to norepinephrine (NE)-mediated regulation of thermogenesis have been a topic of debate. Here we identify sympathetic neuron-associated macrophages ...(SAMs) as a population of cells that mediate clearance of NE via expression of solute carrier family 6 member 2 (SLC6A2), an NE transporter, and monoamine oxidase A (MAOA), a degradation enzyme. Optogenetic activation of the sympathetic nervous system (SNS) upregulates NE uptake by SAMs and shifts the SAM profile to a more proinflammatory state. NE uptake by SAMs is prevented by genetic deletion of Slc6a2 or inhibition of the encoded transporter. We also observed an increased proportion of SAMs in the SNS of two mouse models of obesity. Genetic ablation of Slc6a2 in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis, and leads to substantial and sustained weight loss in obese mice. We further show that this pathway is conserved, as human sympathetic ganglia also contain SAMs expressing the analogous molecular machinery for NE clearance, which thus constitutes a potential target for obesity treatment.
Superoxide anions colliding with benzene molecules at impact energies from 200 to 900 eV are reported for the first time to form massive complexes. With the aid of quantum chemistry calculations, we ...propose a mechanism in which a sudden double ionization of benzene and the subsequent electrostatic attraction between the dication and the anion form a stable covalently bonded C
H
O
molecule, that evolves towards the formation of benzene-diol conformers. These findings lend support to a model presenting a new high energy anion-driven chemistry as an alternative way to form complex molecules.
Continuous spike–wave of sleep (CSWS) syndrome is one of the most common epileptic encephalopathies of childhood. Because the associated cognitive/behavioral disturbances relate more to the amount of ...spike activity than of seizures, methods of spike quantification gained relevance in diagnosis and monitoring treatment. The conventional methodology for quantification of spike index (SI) relies on repeated full 10–20 long-term ambulatory electroencephalography (aEEG), which is both expensive and poorly tolerated.
The objectives of this study were to demonstrate the clinical value of repeated SI assessments in CSWS and to build and validate a wearable device allowing inexpensive and well-tolerated, repeated quantifications.
A group of N = 38 patients with CSWS were submitted to repeated SI quantifications based on aEEG, as seen fit by the medical clinical assistant. Responses to therapy with corticosteroids (N = 10), sulthiame (N = 7), and the ketogenic diet (N = 3) were monitored. We used a conventional method based on a semiautomatic template match spike search. The individual variability in time spans of days (N = 4) or months (N = 10) was assessed and used to determine the meaningful neurophysiological responses to the diverse therapies.
A wearable device capable of recording 2 bipolar EEG channels for 24 h was used to simplify SI quantification.
Corticosteroids produced the most powerful SI reduction, but a large individual variability in both amount and time of onset of clinical response with some patients exhibiting recurrence shortly after therapy. A more frequent sampling of SI would provide a more accurate follow-up, with clinical benefit.
The comparison of the SI obtained from standard 10–20 electrodes and 2 bipolar EEG channel subsets in aEEG or between the 10–20 and simultaneous wearable recordings, demonstrated that the new method provides an accurate SI quantification.
A wearable EEG device with 2 bipolar channels simplifies the process of obtaining repeated SI quantification allowing a more accurate follow-up of spike activity in the clinical setting.
•CSWS is a difficult to treat epileptic encephalopathy of childhood.•The spike index (SI) is widely used clinically for diagnosis and therapy.•A significant variability in time course of response to therapy is common.•Repeated long-term EEGs are required for monitoring but are poorly tolerated.•We validate a small wearable EEG device improving repeated SI acquisitions.
Mycobacterium ulcerans
causes Buruli Ulcer, a neglected infectious skin disease that typically progresses from an early non-ulcerative lesion to an ulcer with undermined edges. If not promptly ...treated, these lesions can lead to severe disfigurement and disability. The standard antibiotic regimen for Buruli Ulcer treatment has been oral rifampicin combined with intramuscular streptomycin administered daily for 8 weeks. However, there has been a recent shift toward replacing streptomycin with oral clarithromycin. Despite the advantages of this antibiotic regimen, it is limited by low compliance, associated side effects, and refractory efficacy for severe ulcerative lesions. Therefore, new drug candidates with a safer pharmacological spectrum and easier mode of administration are needed. Statins are lipid-lowering drugs broadly used for dyslipidemia treatment but have also been reported to have several pleiotropic effects, including antimicrobial activity against fungi, parasites, and bacteria. In the present study, we tested the susceptibility of
M. ulcerans
to several statins, namely atorvastatin, simvastatin, lovastatin and fluvastatin. Using broth microdilution assays and cultures of
M. ulcerans
-infected macrophages, we found that atorvastatin, simvastatin and fluvastatin had antimicrobial activity against
M. ulcerans
. Furthermore, when using the
in vitro
checkerboard assay, the combinatory additive effect of atorvastatin and fluvastatin with the standard antibiotics used for Buruli Ulcer treatment highlighted the potential of statins as adjuvant drugs. In conclusion, statins hold promise as potential treatment options for Buruli Ulcer. Further studies are necessary to validate their effectiveness and understand the mechanism of action of statins against
M. ulcerans
.
Developing innovative systems and operations to monitor forests and send alerts in dangerous situations, such as fires, has become, over the years, a necessary task to protect forests. In this work, ...a Wireless Sensor Network (WSN) is employed for forest data acquisition to identify abrupt anomalies when a fire ignition starts. Even though a low-power LoRaWAN network is used, each module still needs to save power as much as possible to avoid periodic maintenance since a current consumption peak happens while sending messages. Moreover, considering the LoRaWAN characteristics, each module should use the bandwidth only when essential. Therefore, four algorithms were tested and calibrated along real and monitored events of a wildfire. The first algorithm is based on the Exponential Smoothing method, Moving Averages techniques are used to define the other two algorithms, and the fourth uses the Least Mean Square. When properly combined, the algorithms can perform a pre-filtering data acquisition before each module uses the LoRaWAN network and, consequently, save energy if there is no necessity to send data. After the validations, using Wildfire Simulation Events (WSE), the developed filter achieves an accuracy rate of 0.73 with 0.5 possible false alerts. These rates do not represent a final warning to firefighters, and a possible improvement can be achieved through cloud-based server algorithms. By comparing the current consumption before and after the proposed implementation, the modules can save almost 53% of their batteries when is no demand to send data. At the same time, the modules can maintain the server informed with a minimum interval of 15 min and recognize abrupt changes in 60 s when fire ignition appears.
The salivary glands play a central role in the secretion of saliva, whose composition and volume affect oral and overall health. A lesser-explored dimension encompasses the possible changes in ...salivary gland proteomes in response to fluctuations in sex hormone levels. This study aimed to examine the effects of chronic exposure to testosterone on salivary gland remodeling, particularly focusing on proteomic adaptations. Therefore, male Wistar rats were implanted with subcutaneous testosterone-releasing devices at 14 weeks of age. Their submandibular glands were histologically and molecularly analyzed 47 weeks later. The results underscored a significant increase in gland mass after testosterone exposure, further supported by histologic evidence of granular duct enlargement. Despite increased circulating sex hormones, there was no detectable shift in the tissue levels of estrogen alpha and androgen receptors. GeLC-MS/MS and subsequent bioinformatics identified 308 proteins in the submandibular glands, 12 of which were modulated by testosterone. Of note was the pronounced upregulation of Klk3 and the downregulation of Klk6 and Klk7 after testosterone exposure. Protein-protein interaction analysis with the androgen receptor suggests that Klk3 is a potential target of androgenic signaling, paralleling previous findings in the prostate. This exploratory analysis sheds light on the response of salivary glands to testosterone exposure, providing proteome-level insights into the associated weight and histological changes.
Colorectal cancer is one of the most common gastrointestinal malignancies in humans, affecting approximately 1.8 million people worldwide. This disease has a major social impact and high treatment ...costs. Animal models allow us to understand and follow the colon cancer progression; thus, in vivo studies are essential to improve and discover new ways of prevention and treatment. Dietary natural products have been under investigation for better and natural prevention, envisioning to show their potential. This manuscript intends to provide the readers a review of rodent colorectal cancer models available in the literature, highlighting their advantages and disadvantages, as well as their potential in the evaluation of several drugs and natural compounds' effects on colorectal cancer.
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•Rifampicin and streptomycin delivery system for Buruli ulcer topical treatment.•Delivery system with a porous structure and a high water uptake ability.•Incorporated antibiotics ...remained active and were released in a controlled manner.•Cytotoxicity of antibiotics was reduced after incorporation into delivery system.•Proposed system is a promising strategy for topical treatment of Buruli ulcer.
Skin infection by Mycobacterium ulcerans causes Buruli ulcer (BU) disease, a serious condition that significantly impact patient’ health and quality of life and can be very difficult to treat. Treatment of BU is based on daily systemic administration of antibiotics for at least 8 weeks and presents drawbacks associated with the mode and duration of drug administration and potential side effects. Thus, new therapeutic strategies are needed to improve the efficacy and modality of BU therapeutics, resulting in a more convenient and safer antibiotic regimen. Hence, we developed a dual delivery system based on poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) microparticles and a gellan gum (GG) hydrogel for delivery of rifampicin (RIF) and streptomycin (STR), two antibiotics used for BU treatment. RIF was successfully loaded into PHBV microparticles, with an encapsulation efficiency of 43%, that also revealed a mean size of 10 µm, spherical form and rough topography. These microparticles were further embedded in a GG hydrogel containing STR. The resultant hydrogel showed a porous microstructure that conferred a high water retention capability (superior to 2000%) and a controlled release of both antibiotics. Also, biological studies revealed antibacterial activity against M. ulcerans, and a good cytocompatibility in a fibroblast cell line. Thus, the proposed drug delivery system can constitute a potential topical approach for treatment of skin ulcers caused by BU disease.
Lactic acid bacteria (LAB) are a promising solution to reduce exposure to dietary mycotoxins because of the unique mycotoxin decontaminating characteristic of some LAB. Ochratoxin A (OTA) is one of ...the most prominent mycotoxins found in agricultural commodities. The present work reports on the ability of Pediococcus parvulus strains that were isolated from Douro wines that spontaneously underwent malolactic fermentation to detoxify OTA. These strains were identified and characterised using a polyphasic approach that employed both phenotypic and genotypic methods. When cultivated on OTA-supplemented MRS media, OTA was biodegraded into OTα by certain P. parvulus strains. The presence of OTα was confirmed using LC–MS/MS. The conversion of OTA into OTα indicates that the OTA amide bond was hydrolysed by a putative peptidase. The rate of OTA biodegradation was found to be dependent on the inoculum size and on the incubation temperature. Adsorption assays with dead P. parvulus cells showed that approximately 1.3%±1.0 of the OTA was adsorbed onto cells wall, which excludes this mechanism in the elimination of OTA by strains that degrades OTA. Under optimum conditions, 50% and 90% of OTA were degraded in 6 and 19h, respectively. Other LAB strains that belonged to different species were tested but did not degrade OTA. OTA biodegradation by P. parvulus UTAD 473 was observed in grape must. Because some P. parvulus strains have relevant probiotic properties, the strains that were identified could be particularly relevant to food and feed applications to counteract the toxic effects of OTA.
•Pediococcus parvulus strains isolated from Douro wines could biodegrade OTA into OTα.•OTα was confirmed using LC–MS/MS.•Adsorption was not involved in the elimination of OTA by the strains.•50% and 90% of OTA were degraded by P. parvulus in 6 and 19h, respectively.•P. parvulus could degrade OTA in grape must.
In this study, novel experimental total electron detachment cross sections for O
collisions with benzene molecules are reported for the impact energy range (10-1000 eV), as measured with a ...transmission beam apparatus. By analysing the positively charged species produced during the collision events, relative total ionisation cross sections were derived in the incident energy range of 160-900 eV. Relative partial ionisation cross sections for fragments with
/
≤ 78 u were also given in this energy range. We also confirmed that heavier compounds (
/
> 78 u) formed for impact energies between 550 and 800 eV. In order to further our knowledge about the collision dynamics governing the fragmentation of such heavier molecular compounds, we performed molecular dynamics calculations within the framework of the Density Functional Theory (DFT). These results demonstrated that the fragmentation of these heavier compounds strongly supports the experimental evidence of
/
= 39-42, 50, 60 (u) cations formation, which contributed to the broad local maximum in the total ionisation observed from 550 to 800 eV. This work reveals the reactivity induced by molecular anions colliding with hydrocarbons at high energies, processes that can take place in the interstellar medium under various local conditions.
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