•Microglia express receptors for neuromodulators in vivo and in culture.•Neuromodulators modulate microglial cell motility, phagocytic activity, migration.•Neuromodulators modulate microglial immune ...polarization.•Some of the effects of neuromodulators on CNS development and homeostasis might be performed through their modulation of microglia.
Microglial cells, the brain resident macrophages, participate to brain development and function and help maintaining its homeostasis. To play these roles, they need to detect and adapt to modifications of their environment, including changes in the activity of neurons. The neuromodulators serotonin, dopamine, norepinephrine, acetylcholine and histamine are synthesized and released by specialized neurons to coordinate the activity of other neurons in different regions.
In this review, we summarize the current evidence obtained in vitro or in vivo that neuromodulators act on microglia. On the short term, they can modify their motility, morphology and phagocytic activity; on the mid-long term they can modulate their transition between different immune activation states. Lastly, we review some recent data suggesting that these regulations of microglia by neuromodulators are involved in vivo in some aspects of central nervous system development, function and homeostasis.
We propose to repeatedly load laser-cooled molecules into optical tweezers, and transfer them to storage states that are rotationally excited by two additional quanta. Collisional loss of molecules ...in these storage states is suppressed, and a dipolar blockade prevents the accumulation of more than one molecule. Applying three cycles loads tweezers with single molecules at an 80% success rate, limited by residual collisional loss. This improved loading efficiency reduces the time needed for rearrangement of tweezer arrays, which would otherwise limit the scalability of neutral molecule quantum computers.
Despite the critical need for non-invasive tools to improve monitoring of wildlife populations, especially for endangered and elusive species, faecal genetic sampling has not been adopted as regular ...practice, largely because of the associated technical challenges and cost. Substantial work needs to be undertaken to refine sample collection and preparation methods in order to improve sample set quality and provide cost-efficient tools that can effectively support wildlife management. In this study, we collected an extensive set of forest elephant (Loxodonta cyclotis) faecal samples throughout Gabon, Central Africa, and prepared them for genotyping using 107 single-nucleotide polymorphism assays. We developed a new quantitative polymerase chain reaction (PCR) assay targeting a 130-bp nuclear DNA fragment and demonstrated its suitability for degraded samples in all three elephant species. Using this assay to compare the efficacy of two sampling methods for faecal DNA recovery, we found that sampling the whole surface of a dung pile with a swab stored in a small tube of lysis buffer was a convenient method producing high extraction success and DNA yield. We modelled the influence of faecal quality and storage time on DNA concentration in order to provide recommendations for optimized collection and storage. The maximum storage time to ensure 75% success was two months for samples collected within 24 hours after defecation and extended to four months for samples collected within one hour. Lastly, the real-time quantitative PCR assay allowed us to predict genotyping success and pre-screen DNA samples, thus further increasing the cost-efficiency of our approach. We recommend combining the validation of an efficient sampling method, the build of in-country DNA extraction capacity for reduced storage time and the development of species-specific quantitative PCR assays in order to increase the cost-efficiency of routine non-invasive DNA analyses and expand the use of next-generation markers to non-invasive samples.
In this phase 2 study, single oral doses of gepotidacin were ≥95% effective for bacterial eradication in culture-proven uncomplicated urogenital gonorrhea. New antibiotics for drug-resistant ...Neisseria gonorrhoeae are urgently needed. With additional evaluation, gepotidacin may provide an alternative therapeutic option.
Abstract
Background
In this phase 2 study, we evaluated the efficacy and safety of oral gepotidacin, a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor, for the treatment of uncomplicated urogenital gonorrhea.
Methods
Adult participants with suspected urogenital gonorrhea were enrolled and completed baseline (day 1) and test-of-cure (days 4-8) visits. Pretreatment and posttreatment urogenital swabs were collected for Neisseria gonorrhoeae (NG) culture and susceptibility testing. Pharyngeal and rectal swab specimens were collected if there were known exposures. Participants were stratified by gender and randomized 1:1 to receive a 1500-mg or 3000-mg single oral dose of gepotidacin.
Results
The microbiologically evaluable population consisted of 69 participants, with NG isolated from 69 (100%) urogenital, 2 (3%) pharyngeal, and 3 (4%) rectal specimens. Microbiological eradication of NG was achieved by 97%, 95%, and 96% of participants (lower 1-sided exact 95% confidence interval bound, 85.1%, 84.7%, and 89.1%, respectively) for the 1500-mg, 3000-mg, and combined dose groups, respectively. Microbiological cure was achieved in 66/69 (96%) urogenital infections. All 3 failures were NG isolates that demonstrated the highest observed gepotidacin minimum inhibitory concentration of 1 µg/mL and a common gene mutation. At the pharyngeal and rectal sites, 1/2 and 3/3 NG isolates, respectively, demonstrated microbiological cure. There were no treatment-limiting adverse events for either dose.
Conclusions
This study demonstrated that single, oral doses of gepotidacin were ≥95% effective for bacterial eradication of NG in adult participants with uncomplicated urogenital gonorrhea.
Clinical Trials Registration
NCT02294682.
Antibiotics are the current standard-of-care treatment for uncomplicated urinary tract infections (uUTIs). However, increasing rates of bacterial antibiotic resistance necessitate novel therapeutic ...options. Gepotidacin is a first-in-class triazaacenaphthylene antibiotic that selectively inhibits bacterial DNA replication by interaction with the bacterial subunits of DNA gyrase (GyrA) and topoisomerase IV (ParC). Gepotidacin is currently in clinical development for the treatment of uUTIs and other infections. In this article, we review data for gepotidacin from nonclinical studies, including
activity,
animal efficacy, and pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) models that informed dose selection for phase III clinical evaluation of gepotidacin. Based on this translational package of data, a gepotidacin 1,500-mg oral dose twice daily for 5 days was selected for two ongoing, randomized, multicenter, parallel-group, double-blind, double-dummy, active-comparator phase III clinical studies evaluating the safety and efficacy of gepotidacin in adolescent and adult female participants with uUTIs (ClinicalTrials.gov identifiers NCT04020341 and NCT04187144).
Angstrom resolution images of human tooth enamel (HTE) crystallites were obtained using aberration-corrected high-resolution transmission electron microscopy and atomic-resolution scanning ...transmission electron microscopy in the modes of bright field, annular dark field, and high-angle annular dark-field. Images show that the central dark line (CDL) defect observed around the center of the HTE crystals is a site for caries formation in the HTE and has a thickness of ~0.2 nm. Results also suggest that the CDL goes through one of the OH− planes.
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