Региоселективный синтез и свойства ацетильных производных фенолгликозидов

Региоселективный синтез и свойства ацетильных производных фенолгликозидов. Работа посвящена выявлению реакционной способности при кислотном дезацетилировании с использованием HCl / EtOH в CHCl3, которая приводит к дезацетилированию на O-3, O-4 и O-6. Описанный реагент оказался общим и уникальным, и была получена серия 2-О-ацетиларилгликозидов. Вообще, частично ацетилированные арилгликозиды широко встречаются в природе. В частности, можно найти множество примеров 2-O-ацетиларилгликозидов.Regioselective synthesis and properties of acetyl derivatives of phenol glycosides. The thesis is devoted to the detection of reactivity during acid deacetylation using HCl / EtOH in CHCl3, which leads to deacetylation at O-3, O-4 and O-6. The described reagent proved to be general and unique and the series of 2-О-acetyl aryl glycosides were prepared. Generally, partially acetylated aryl glycosides are widely found in nature. Particularly, many examples of 2-O-acetyl aryl glycosides can be found

EEG microstate quantifiers and state space descriptors during anaesthesia in patients with postoperative delirium: a descriptive analysis.

Postoperative delirium is a serious sequela of surgery and surgery-related anaesthesia. One recommended method to prevent postoperative delirium is using bi-frontal EEG recording. The single, processed index of depth of anaesthesia allows the anaesthetist to avoid episodes of suppression EEG and excessively deep anaesthesia. The study data presented here were based on multichannel (19 channels) EEG recordings during anaesthesia. This enabled the analysis of various parameters of global electrical brain activity. These parameters were used to compare microstate topographies under anaesthesia with those in healthy volunteers and to analyse changes in microstate quantifiers and EEG global state space descriptors with increasing exposure to anaesthesia. Seventy-three patients from the Surgery Depth of Anaesthesia and Cognitive Outcome study (SRCTN 36437985) received intraoperative multichannel EEG recordings. Altogether, 720 min of artefact-free EEG data, including 210 min (29.2%) of suppression EEG, were analysed. EEG microstate topographies, microstate quantifiers (duration, frequency of occurrence and global field power) and the state space descriptors sigma (overall EEG power), phi (generalized frequency) and omega (number of uncorrelated brain processes) were evaluated as a function of duration of exposure to anaesthesia, suppression EEG and subsequent development of postoperative delirium. The major analyses involved covariate-adjusted linear mixed-effects models. The older (71 ± 7 years), predominantly male (60%) patients received a median exposure of 210 (range: 75-675) min of anaesthesia. During seven postoperative days, 21 patients (29%) developed postoperative delirium. Microstate topographies under anaesthesia resembled topographies from healthy and much younger awake persons. With increasing duration of exposure to anaesthesia, single microstate quantifiers progressed differently in suppression or non-suppression EEG and in patients with or without subsequent postoperative delirium. The most pronounced changes occurred during enduring suppression EEG in patients with subsequent postoperative delirium: duration and frequency of occurrence of microstates C and D progressed in opposite directions, and the state space descriptors showed a pattern of declining uncorrelated brain processes (omega) combined with increasing EEG variance (sigma). With increasing exposure to general anaesthesia, multiple changes in the dynamics of microstates and global EEG parameters occurred. These changes varied partly between suppression and non-suppression EEG and between patients with or without subsequent postoperative delirium. Ongoing suppression EEG in patients with subsequent postoperative delirium was associated with reduced network complexity in combination with increased overall EEG power. Additionally, marked changes in quantifiers in microstate C and in microstate D occurred. These putatively adverse intraoperative trajectories in global electrical brain activity may be seen as preceding and ultimately predicting postoperative delirium

Does Prenatal Stress Shape Postnatal Resilience? – An Epigenome-Wide Study on Violence and Mental Health in Humans

Stress during pregnancy widely associates with epigenetic changes and psychiatric problems during childhood. Animal studies, however, show that under specific postnatal conditions prenatal stress may have other, less detrimental consequences for the offspring. Here, we studied mental health and epigenome-wide DNA methylation in saliva following intimate partner violence (IPV) during pregnancy in São Gonçalo, a Brazilian city with high levels of violence. Not surprisingly, mothers exposed to pregnancy IPV expressed elevated depression, PTSD and anxiety symptoms. Children had similar psychiatric problems when they experienced maternal IPV after being born. More surprisingly, when maternal IPV occurred both during (prenatal) and after pregnancy these problems were absent. Following prenatal IPV, genomic sites in genes encoding the glucocorticoid receptor (NR3C1) and its repressor FKBP51 (FKBP5) were among the most differentially methylated and indicated an enhanced ability to terminate hormonal stress responses in prenatally stressed children. These children also showed more DNA methylation in heterochromatin-like regions, which previously has been associated with stress/disease resilience. A similar relationship was seen in prenatally stressed middle-eastern refugees of the same age as the São Gonçalo children but exposed to postnatal war-related violence. While our study is limited in location and sample size, it provides novel insights on how prenatal stress may epigenetically shape resilience in humans, possibly through interactions with the postnatal environment. This translates animal findings and emphasizes the importance to account for population differences when studying how early life gene–environment interactions affects mental health

A novel nuclear antigen

The human oestrogen receptor (hER) mediates some effects of the steroid hormone oestrogen and functions as a ligand-dependent transcription factor in the nuclei of oestrogen-sensitive cells. The measurement of hER levels in breast cancer biopsies provides useful clinical information regarding therapy and prognosis. The current study describes a monoclonal antibody raised against hER aa 497-507 which recognises a novel nuclear antigen. Monoclonal antibodies were raised by immunising mice with a synthetic fragment of the hER (aa 497-507) conjugated to keyhole lymphocyte haemocyanin. Thirty antibody secreting hybridomas were identified. Hybridoma supernatants were characterised by enzyme-linked immunosorbent assay (ELISA), immunological staining using MCF-7 cells, binding studies, and SDS-PAGE Western blotting. One supernatant (15F6) displayed nuclear staining in fixed MCF -7 cells. Staining could be abolished by pre-incubation of the supernatant with the aa 497-507 peptide and peptide conjugates, but not with an unrelated hER peptide (aa 256-275). This antibody also stained the nuclei of hER negative breast cell lines MDA-MB-231 and MDA-MB-330, the breast cell line T47D, and liver cell line HepG2. Immunological staining of human tissue sections reveal the antigen to be present in the nuclei of keratocytes in skin and tubule and luminal endothelial cells of the kidney. The antibody identified a 120 kD band on Western blots with cytosols prepared from human breast cell lines and in solubilised cells. The antibody does not precipitate 16a-iodooestradiol-labelled ER from MCF-7 cells. Expression-linked screening of the MCF-7 cDNA library with antibody 15F6 identified nine positive clones. Antibody staining could be blocked by pre-incubating the antibody with hER aa 497-507-BSA conjugate, but not with an unrelated hER peptide conjugate. The (260 bp) clones were found to be identical. Submission of sequence to BLAST protein and nucleotide databases revealed a lack of homology to known proteins and genes. Sequence was matched to expressed sequence tags (ESTs) from brain, liver/spleen, uterus, ovary, colon, heart, and placenta. To further define the epitope of antibody 15F6, the sequence was translated and three peptides containing potential epitopes, comparable to the hER aa 497-507 region, were synthesised and tested by ELISA. The putative epitope was shown to be contained within one of these peptides

Regional sociocultural differences as important correlate of physical activity and sedentary behaviour in Swiss preschool children

Regional differences in physical activity in school-aged children and adults even within one country with the same political and health care system have been observed and could not be explained by sociodemographic or individual variables. We analysed whether such differences were already present in preschool children.; Swiss children from 84 childcare centres in five cantons (Aargau, Bern, Fribourg, Vaud, Zurich) comprising about 50% of the population of the country participated. Physical activity was quantified with accelerometers (ActiGraph, wGT3X-BT) and potential correlates were assessed with measurements at the childcare centre or questionnaires. Mixed regression models were used to test associations between potential correlates of total physical activity (TPA), moderate-to-vigorous physical activity (MVPA), light physical activity (LPA) or sedentary behaviour with a special focus on regional differences.; 394 of 476 children (83%) provided valid physical activity data (at least 2 weekdays and 1 weekend day with 10 h recording; mean age 3.9 ± 0.7 years, 54% boys) with 26% and 74% living in the French- and German-speaking parts of Switzerland, respectively. Days consisted of (mean ± standard deviation) 1.5 ± 0.5 h MVPA, 5.0 ± 0.6 h LPA, and 6.3 ± 0.8 h sedentary behaviour with an average of 624 ± 150 counts/min TPA. TPA and MVPA (but not sedentary behaviour or LPA) increased with age, were higher in boys and children with better motor skills. Despite controlling for individual characteristics, familial factors and childcare exposure, children from the French-speaking part of Switzerland showed 13% less TPA, 14% less MVPA, 6% less LPA and 8% more sedentary behaviour than German-speaking children.; Beside motor skills and non-modifiable individual factors, the regional sociocultural difference was the most important correlate of phyical activity and sedentary behaviour. Therefore, regionally adapted public health strategies may be needed

DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport.

The small intestine is a dynamic and complex organ that is characterized by constant epithelium turnover and crosstalk among various cell types and the microbiota. Lymphatic capillaries of the small intestine, called lacteals, play key roles in dietary fat absorption and the gut immune response; however, little is known about the molecular regulation of lacteal function. Here, we performed a high-resolution analysis of the small intestinal stroma and determined that lacteals reside in a permanent regenerative, proliferative state that is distinct from embryonic lymphangiogenesis or quiescent lymphatic vessels observed in other tissues. We further demonstrated that this continuous regeneration process is mediated by Notch signaling and that the expression of the Notch ligand delta-like 4 (DLL4) in lacteals requires activation of VEGFR3 and VEGFR2. Moreover, genetic inactivation of Dll4 in lymphatic endothelial cells led to lacteal regression and impaired dietary fat uptake. We propose that such a slow lymphatic regeneration mode is necessary to match a unique need of intestinal lymphatic vessels for both continuous maintenance, due to the constant exposure to dietary fat and mechanical strain, and efficient uptake of fat and immune cells. Our work reveals how lymphatic vessel responses are shaped by tissue specialization and uncover a role for continuous DLL4 signaling in the function of adult lymphatic vasculature

DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport

The small intestine is a dynamic and complex organ that is characterized by constant epithelium turnover and crosstalk among various cell types and the microbiota. Lymphatic capillaries of the small intestine, called lacteals, play key roles in dietary fat absorption and the gut immune response; however, little is known about the molecular regulation of lacteal function. Here, we performed a high-resolution analysis of the small intestinal stroma and determined that lacteals reside in a permanent regenerative, proliferative state that is distinct from embryonic lymphangiogenesis or quiescent lymphatic vessels observed in other tissues. We further demonstrated that this continuous regeneration process is mediated by Notch signaling and that the expression of the Notch ligand delta-like 4 (DLL4) in lacteals requires activation of VEGFR3 and VEGFR2. Moreover, genetic inactivation of Dll4 in lymphatic endothelial cells led to lacteal regression and impaired dietary fat uptake. We propose that such a slow lymphatic regeneration mode is necessary to match a unique need of intestinal lymphatic vessels for both continuous maintenance, due to the constant exposure to dietary fat and mechanical strain, and efficient uptake of fat and immune cells. Our work reveals how lymphatic vessel responses are shaped by tissue specialization and uncover a role for continuous DLL4 signaling in the function of adult lymphatic vasculature

Regional sociocultural differences as important correlate of physical activity and sedentary behaviour in Swiss preschool children

QUESTION: Regional differences in physical activity in school-aged children and adults even within one country with the same political and health care system have been observed and could not be explained by sociodemographic or individual variables. We analysed whether such differences were already present in preschool children. METHODS: Swiss children from 84 childcare centres in five cantons (Aargau, Bern, Fribourg, Vaud, Zurich) comprising about 50% of the population of the country participated. Physical activity was quantified with accelerometers (ActiGraph, wGT3X-BT) and potential correlates were assessed with measurements at the childcare centre or questionnaires. Mixed regression models were used to test associations between potential correlates of total physical activity (TPA), moderate-to-vigorous physical activity (MVPA), light physical activity (LPA) or sedentary behaviour with a special focus on regional differences. RESULTS: 394 of 476 children (83%) provided valid physical activity data (at least 2 weekdays and 1 weekend day with 10 h recording; mean age 3.9 ± 0.7 years, 54% boys) with 26% and 74% living in the French- and German-speaking parts of Switzerland, respectively. Days consisted of (mean ± standard deviation) 1.5 ± 0.5 h MVPA, 5.0 ± 0.6 h LPA, and 6.3 ± 0.8 h sedentary behaviour with an average of 624 ± 150 counts/min TPA. TPA and MVPA (but not sedentary behaviour or LPA) increased with age, were higher in boys and children with better motor skills. Despite controlling for individual characteristics, familial factors and childcare exposure, children from the French-speaking part of Switzerland showed 13% less TPA, 14% less MVPA, 6% less LPA and 8% more sedentary behaviour than German-speaking children. CONCLUSION: Beside motor skills and non-modifiable individual factors, the regional sociocultural difference was the most important correlate of phyical activity and sedentary behaviour. Therefore, regionally adapted public health strategies may be needed

Recommendations, guidelines, and best practice for the use of human induced pluripotent stem cells for neuropharmacological studies of neuropsychiatric disorders

The number of individuals suffering from neuropsychiatric disorders (NPDs) has increased worldwide, with 3 million disability-adjusted life-years calculated in 2019. Though research using various approaches including genetics, imaging, clinical and animal models has advanced our knowledge regarding NPDs, we still lack basic knowledge regarding the underlying pathophysiological mechanisms. Moreover, there is an urgent need for highly effective therapeutics for NPDs. Human induced pluripotent stem cells (hiPSCs) generated from somatic cells enabled scientists to create brain cells in a patient-specific manner. However, there are challenges to the use of hiPSCs that need to be addressed. In the current paper, consideration of best practices for neuropharmacological and neuropsychiatric research using hiPSCs will be discussed. Specifically, we provide recommendations for best practice in patient recruitment, including collecting demographic, clinical, medical (before and after treatment and response), diagnostic (including scales) and genetic data from the donors. We highlight considerations regarding donor genetics and sex, in addition to discussing biological and technical replicates. Furthermore, we present our views on selecting control groups/lines, experimental designs, and considerations for conducting neuropharmacological studies using hiPSC-based models in the context of NPDs. In doing so, we explore key issues in the field concerning reproducibility, statistical analysis, and how to translate in vitro studies into clinically relevant observations. The aim of this article is to provide a key resource for hiPSC researchers to perform robust and reproducible neuropharmacological studies, with the ultimate aim of improving identification and clinical translation of novel therapeutic drugs for NPDs

Regulatory domain selectivity in the cell-type specific PKN-dependence of cell migration

The mammalian protein kinase N (PKN) family of Serine/Threonine kinases comprises three isoforms, which are targets for Rho family GTPases. Small GTPases are major regulators of the cellular cytoskeleton, generating interest in the role(s) of specific PKN isoforms in processes such as cell migration and invasion. It has been reported that PKN3 is required for prostate tumour cell invasion but not PKN1 or 2. Here we employ a cell model, the 5637 bladder tumour cell line where PKN2 is relatively highly expressed, to assess the potential redundancy of these isoforms in migratory responses. It is established that PKN2 has a critical role in the migration and invasion of these cells. Furthermore, using a PKN wild-type and chimera rescue strategy, it is shown that PKN isoforms are not simply redundant in supporting migration, but appear to be linked through isoform specific regulatory domain properties to selective upstream signals. It is concluded that intervention in PKNs may need to be directed at multiple isoforms to be effective in different cell types