Cholesterol and oxysterols in retinal neuron-glia interactions: relevance for glaucoma

Cholesterol is an essential component of cellular membranes, crucial for maintaining their structural and functional integrity. It is especially important for nervous tissues, including the retina, which rely on high amounts of plasma membranes for the transmission of the nervous signal. While cholesterol is by far the most abundant sterol, the retina also contains cholesterol precursors and metabolites, especially oxysterols, which are bioactive molecules. Cholesterol lack or excess is deleterious and some oxysterols are known for their effect on neuron survival. Cholesterol homeostasis must therefore be maintained. Retinal glial cells, especially Müller cells, the principal glial cells of the vertebrate retina, provide mechanical, nutritional, and metabolic support for the neighboring neurons. Several pieces of evidence indicate that Müller cells are major actors of cholesterol homeostasis in the retina, as it is known for other glial cells in the brain. This process is based on a close cooperation with neurons, and sterols can be signaling molecules participating in glia-neuron interactions. While some implication of cholesterol in age-related macular degeneration is now recognized, based on epidemiological and laboratory data, evidence for its role in glaucoma is still scarce. The association between cholesterolemia and glaucoma is controversial, but experimental data suggest that sterols could take part in the pathological processes. It has been demonstrated that Müller glial cells are implicated in the development of glaucoma through an ambivalent reactive retinal gliosis process. The early steps contribute to maintaining retinal homeostasis and favor the survival of ganglion cells, which are targeted during glaucoma. If gliosis persists, dysregulation of the neuroprotective functions, cytotoxic effects of gliotic Müller cells and disruption of glia-neuron interactions lead to an acceleration of ganglion cell death. Sterols could play a role in the glial cell response to glaucomatous injury. This represents an understudied but attractive topic to better understand glaucoma and conceive novel preventive or curative strategies. The present review describes the current knowledge on i) sterol metabolism in retinal glial cells, ii) the potential role of cholesterol in glaucoma, and iii) the possible relationships between cholesterol and oxysterols, glial cells and glaucoma. Focus is put on glia-neuron interactions

Report on the 2022 excavations at Wogan Cavern (Pembroke, Pembrokeshire, UK)

In a previous article in this journal (Dinnis et al., 2022), we described the first season of archaeological excavations at Wogan Cavern (Pembroke, southwest Wales). Although based on excavation of a very small volume of deposits, we suggested that the sediments in Wogan Cavern may have very good potential for preserving archaeological remains. Specifically, an intact early Holocene archaeological layer and underlying, bone-bearing Pleistocene deposits encouraged us to believe that the cave might be an important early prehistoric site. Here, we provide an update on our previous work, detailing the findings of the 2022 excavation season. The 2022 work identified several phases of historic and prehistoric activity. The early Holocene archaeological layer containing diagnostic Mesolithic artefacts, found previously in the eastern part of the cave, was shown to extend towards the centre of the cave. Stratigraphically lower deposits dating to the Pleistocene, previously demonstrated close to the cave's eastern wall, were also shown to extend towards the cave's centre. Excavation of the Pleistocene deposits close to the cave's eastern wall revealed evidence for human occupation, with one and possibly two Upper Palaeolithic layers present. The archaeological assemblage(s) from these lower deposits bear similarities to the Palaeolithic stone tool assemblage from the famous Paviland Cave, located c.30 miles (c.50km) to the east. Overall, our 2022 work confirms that Wogan Cavern is an early prehistoric site of national, and potentially international, significance

The archaeological potential of Wogan Cavern (Pembroke, UK):Results of the first fieldwork season

Funding Information: Acknowledgements Many thanks are due to numerous people for their help with our work on Wogan Cavern, including (but not limited to) Jon Williams and the staff at Pembroke Castle, Sian Williams, several colleagues at Dyfed Archaeological Trust, Mark Lewis and Eloise Chapman at Tenby Museum, and Louise Mees at Cadw. We are also grateful to the reviewers for a careful reading of this article and for providing some insightful comments, and to David Lowe, whose comments and advice benefitted the final version of the Paper. The work described here and that planned for the future is funded by the Natural History Museum’s Human Origins Research Fund, the BCRA’s CSTRF scheme, and the Prehistoric Society. ELJ acknowledges the Belspo-ICHIE project for funding her contribution to this research.Peer reviewedPublisher PD

Report on the 2022 excavations at Wogan Cavern (Pembroke, Pembrokeshire, UK)

Publisher Copyright: © 2023 British Cave Research Association. All rights reserved.Peer reviewe

Ancestral TSH mechanism signals summer in a photoperiodic mammal

SummaryIn mammals, day-length-sensitive (photoperiodic) seasonal breeding cycles depend on the pineal hormone melatonin, which modulates secretion of reproductive hormones by the anterior pituitary gland [1]. It is thought that melatonin acts in the hypothalamus to control reproduction through the release of neurosecretory signals into the pituitary portal blood supply, where they act on pituitary endocrine cells [2]. Contrastingly, we show here that during the reproductive response of Soay sheep exposed to summer day lengths, the reverse applies: Melatonin acts directly on anterior-pituitary cells, and these then relay the photoperiodic message back into the hypothalamus to control neuroendocrine output. The switch to long days causes melatonin-responsive cells in the pars tuberalis (PT) of the anterior pituitary to increase production of thyrotrophin (TSH). This acts locally on TSH-receptor-expressing cells in the adjacent mediobasal hypothalamus, leading to increased expression of type II thyroid hormone deiodinase (DIO2). DIO2 initiates the summer response by increasing hypothalamic tri-iodothyronine (T3) levels. These data and recent findings in quail [3] indicate that the TSH-expressing cells of the PT play an ancestral role in seasonal reproductive control in vertebrates. In mammals this provides the missing link between the pineal melatonin signal and thyroid-dependent seasonal biology

Investigation of Concurrent Pneumococcal Meningitis in Two Children Attending the Same Day-Care Center

Only a few clusters of invasive pneumococcal disease have been described globally in children, and most of these cases occurred before pneumococcal vaccination implementation. Two unusual cases of pneumococcal meningitis, occurring in the same daycare center over a 3-day period, were reported. Both cerebrospinal fluid (CSF) were sent to the National reference center for pneumococci. In addition, we decided to perform a pneumococcal carriage study on all children and staff of the daycare center to analyze the pneumococcal serotypes circulating in this DCC and to discuss an antibiotic chemoprophylaxis. CSF culture was positive for pneumococcus, and serotype 25A was identified by latex agglutination. The second case had negative CSF culture, but CSF antigen test and gene amplification results were positive for Streptococcus pneumoniae. Serotype 12F was identified by using molecular biology. The absence of correlation between these strains was confirmed by multi-locus sequence typing. In the carriage study, we included 29 children (median age 1.9 years, interquartile range 1.4–2.5) and 10 adults. Among the children, 24 carried Streptococcus pneumoniae (83%). The main serotypes isolated were 23A for 6 children and 25A for 5 children; serotypes were non-typeable for 3 children. Only 1 of 10 adults tested carried Streptococcus pneumoniae (serotype 12F). Despite this temporo-spatial pattern, the cases were unrelated and not due to carriage of a particular serotype. No specific action has been taken for the other children attending this DCC, and no other case of bacterial meningitis occurred

Rôle des gangliosides dans les perturbations de la prolifération des péricytes rétiniens et des cellules mésangiales rénales : implication dans le développement de la rétinopathie et de la néphropathie diabétiques

La perte des péricytes rétiniens est une des premières altérations de la rétinopathie diabétique. Larrêt du cycle cellulaire, lhypertrophie puis la disparition des cellules mésangiales rénales sont des caractéristiques typiques de la néphropathie diabétique. La voie de la glycation (formation des produits avancés de glycation ou AGE) et la voie de lhexosamine sont deux hypothèses biochimiques proposées pour expliquer les altérations cellulaires des microcomplications du diabète. Dautre part, bien que les gangliosides aient souvent été décrits pour moduler la prolifération cellulaire, leur rôle potentiel dans les perturbations de prolifération caractéristiques de la rétinopathie et de la néphropathie diabétiques a été très peu étudié. Lobjectif de ce travail de thèse a été de déterminer les effets des AGE et dune activation de la voie de lhexosamine, mimée par la glucosamine, sur la prolifération et le métabolisme des gangliosides des péricytes et de cellules mésangiales puis détablir limplication des gangliosides dans ces processus de régulation de la prolifération. Nos résultats ont montré que les AGE et la glucosamine inhibent la prolifération des deux types cellulaires étudiés. De plus, ils ont révélé que la glucosamine bloque le cycle cellulaire et induit lhypertrophie des cellules mésangiales. Dautre part, les AGE comme la glucosamine sont capables de modifier le profil en gangliosides des cellules, en modulant les activités de leurs enzymes de biosynthèse. Enfin, nos observations suggèrent que les gangliosides sont impliqués dans linhibition de la prolifération et lhypertrophie causée par les AGE et la glucosamine dans les péricytes et les cellules mésangiales. Elles présentent ainsi les gangliosides comme un nouveau mécanisme daction des AGE et de la voie de lhexosamine et permettent de proposer les gangliosides, en particulier ceux de la série-a, et la GM3 synthase, comme un mécanisme potentiel commun au développement de la rétinopathie et de la néphropathie diabétiques. Ce travail est un des premiers à suggérer limplication des gangliosides dans les complications microvasculaires du diabète que sont la rétinopathie et la néphropathie diabétiques. Par lintermédiaire des gangliosides, il ouvre des perspectives thérapeutiques nouvelles et communes pour le traitement des deux microcomplications

Sample preparation and analysis of gangliosides and phospholipids from plasma by liquid chromatography coupled to mass spectrometry

Gangliosides (GG) and phospholipids (PL) are two classes of complex and polar lipids exhibiting a wide structural heterogeneity. LC/MS offers an access to this huge diversity but also faces some challenges. Efficient extraction and purification sample methods are thus required to perform accurate and reliable analyses. To this end, GG and PL were extracted from human plasma with three solvent mixtures (CHCl3/MeOH/H2O) of increasing polarity, in comparison with the reference Folch method. GG were further purified with a Phree Phospholipid Removal column, whose sorbent is designed to selectively remove PL. GG and PL classes were then separated under HILIC conditions before analysis using a QqQ mass spectrometer.Our method enabled a fast, straightforward and efficient extraction of both complex lipids, PL and GG. The extraction efficiency was much higher than the Folch method for the especially polar lipids that are GG and Lyso-PC, and similar for the various PL classes (PG, PI, PE, PS, PC, Sphingomyelin). The relative quantitative analysis of GG, performed by single reaction monitoring thanks to their characteristic sialic acid fragment (m/z 290), revealed a massive ion-suppression effect (up to 90%) due to co-elution of PC with the less polar GG. Removal of PL is thus essential for an accurate GG analysis by LC/MS and the Phree Phospholipid Removal column appeared as a powerful tool to achieve this purification step.Our sample preparation method allows the accurate analysis of both GG and PL classes from a single biological extract