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Central retinal artery occlusion (CRAO) is a rare emergency, often affecting individuals over 60, with risk factors such as hypertension, diabetes, and smoking. Hyperbaric oxygen therapy (HBOT), classified as level IIb by the American Heart Association for CRAO, helps maintain retinal oxygenation during ischemic events by diffusing oxygen through choroidal capillaries. While HBOT appears promising for addressing various vision-threatening conditions, including retinal occlusions and diabetic macular edema, it has not been officially approved for these indications. A 70-year-old male presented with painless vision loss in his right eye, noticed upon waking, accompanied by high blood pressure. On examination, light perception was detected in the right eye, and visual acuity in the left was 0.6. Biomicroscopy revealed CRAO in the right eye, with a cherry-red spot, retinal edema, and absent circulation. Optical coherence tomography (OCT) confirmed retinal edema and subretinal fluid. Given that the thrombolysis window had passed, HBOT was initiated within 48 h of presentation. Following the first treatment, the patient experienced improvement in vision, with light perception expanding beyond the peripheral area. CRAO is an ocular emergency, and early treatment is crucial for improving visual outcomes. HBOT, recommended within 6–12 h of diagnosis, has shown promise in restoring vision. In our case, HBOT administered within 48 h led to improved peripheral vision, with the presence of a cherry-red spot on the macula associated with better recovery. While HBOT can have side effects, none were observed here. Despite challenges in conducting large-scale trials, HBOT remains a potentially effective treatment for CRAO, especially if started early. Using oxygen therapy to treat sudden vision loss beyond 24 hours: a case study This report describes a rare eye emergency called central retinal artery occlusion (CRAO), which can cause sudden vision loss. It usually affects older adults and is linked to conditions like high blood pressure, diabetes, and smoking. The patient was treated with hyperbaric oxygen therapy (HBOT). This involves breathing pure oxygen in a pressurized chamber to help deliver oxygen to the retina, even when blood flow is blocked. A 70-year-old man woke up with vision loss in one eye. Tests showed CRAO, and since the usual treatment window had passed, doctors started HBOT within 48 hours. After the first session, the patient noticed some improvement in his vision. Although HBOT is not officially approved for CRAO, this case shows it may help if started early. The patient’s vision improved without any side effects. More research is needed, but HBOT could be a useful option for CRAO when other treatments are not possible.

Endocrine Disrupting Chemicals (EDCs) are man-made compounds that alter functions of the endocrine system. Environmental mixtures of EDCs might have adverse effects on human health, even though their individual concentrations are below regulatory levels of concerns. However, studies identifying and experimentally testing adverse effects of real-life mixtures are scarce. In this study, we aimed at evaluating an epidemiologically identified EDC mixture in an experimental setting to delineate its cellular and epigenetic effects. The mixture was established using data from the Swedish Environmental Longitudinal Mother and child Asthma and allergy (SELMA) study where it was associated with lower birth weight, an early marker for prenatal metabolic programming. This mixture was then tested for its ability to change metabolic programming of human mesenchymal stem cells. In these cells, we assessed if the mixture induced adipogenesis and genome-wide DNA methylation changes. The mixture increased lipid droplet accumulation already at concentrations corresponding to levels measured in the pregnant women of the SELMA study. Furthermore, we identified differentially methylated regions in genes important for adipogenesis and thermogenesis. This study shows that a mixture reflecting human real-life exposure can induce molecular and cellular changes during development that could underlie adverse outcomes.

A novel method for finding linear mappings among word embeddings for several languages, taking as pivot a shared, multilingual embedding space, is proposed in this paper. Previous approaches learned translation matrices between two specific languages, while this method learns translation matrices between a given language and a shared, multilingual space. The system was first trained on bilingual, and later on multilingual corpora as well. In the first case, two different training data were applied: Dinu’s English–Italian benchmark data, and English–Italian translation pairs extracted from the PanLex database. In the second case, only the PanLex database was used. The system performs on English–Italian languages with the best setting significantly better than the baseline system given by Mikolov, and it provides a comparable performance with more sophisticated systems. Exploiting the richness of the PanLex database, the proposed method makes it possible to learn linear mappings among an arbitrary number of languages.

Emerging evidence suggests that the vascular endothelial growth factor receptor 2 (VEGFR2) and protein kinase D1 (PKD1) signaling axis plays a critical role in normal and pathological angiogenesis and inflammation related processes. Despite all efforts, the currently available therapeutic interventions are limited. Prior studies have also proved that a multiple target inhibitor can be more efficient compared to a single target one. Therefore, development of novel inflammatory pathway-specific inhibitors would be of great value. To test this possibility, we screened our molecular library using recombinant kinase assays and identified the previously described compound VCC251801 with strong inhibitory effect on both VEGFR2 and PKD1. We further analyzed the effect of VCC251801 in the endothelium-derived EA.hy926 cell line and in different inflammatory cell types. In EA.hy926 cells, VCC251801 potently inhibited the intracellular activation and signaling of VEGFR2 and PKD1 which inhibition eventually resulted in diminished cell proliferation. In this model, our compound was also an efficient inhibitor of in vitro angiogenesis by interfering with endothelial cell migration and tube formation processes. Our results from functional assays in inflammatory cellular models such as neutrophils and mast cells suggested an anti-inflammatory effect of VCC251801. The neutrophil study showed that VCC251801 specifically blocked the immobilized immune-complex and the adhesion dependent TNF-α -fibrinogen stimulated neutrophil activation. Furthermore, similar results were found in mast cell degranulation assay where VCC251801 caused significant reduction of mast cell response. In summary, we described a novel function of a multiple kinase inhibitor which strongly inhibits the VEGFR2-PKD1 signaling and might be a novel inhibitor of pathological inflammatory pathways.

Background DNA methylation is one way to encode epigenetic information and plays a crucial role in regulating gene expression during embryonic development. DNA methylation marks are established by the DNA methyltransferases and, recently, a mechanism for active DNA demethylation has emerged involving the ten-eleven translocator proteins and thymine DNA glycosylase (TDG). However, so far it is not clear how these enzymes are recruited to, and regulate DNA methylation at, specific genomic loci. A number of studies imply that sequence-specific transcription factors are involved in targeting DNA methylation and demethylation processes. Oestrogen receptor beta (ERβ) is a ligand-inducible transcription factor regulating gene expression in response to the female sex hormone oestrogen. Previously, we found that ERβ deficiency results in changes in DNA methylation patterns at two gene promoters, implicating an involvement of ERβ in DNA methylation. In this study, we set out to explore this involvement on a genome-wide level, and to investigate the underlying mechanisms of this function. Results Using reduced representation bisulfite sequencing, we compared genome-wide DNA methylation in mouse embryonic fibroblasts derived from wildtype and ERβ knock-out mice, and identified around 8000 differentially methylated positions (DMPs). Validation and further characterisation of selected DMPs showed that differences in methylation correlated with changes in expression of the nearest gene. Additionally, re-introduction of ERβ into the knock-out cells could reverse hypermethylation and reactivate expression of some of the genes. We also show that ERβ is recruited to regions around hypermethylated DMPs. Finally, we demonstrate here that ERβ interacts with TDG and that TDG binds ERβ-dependently to hypermethylated DMPs. Conclusion We provide evidence that ERβ plays a role in regulating DNA methylation at specific genomic loci, likely as the result of its interaction with TDG at these regions. Our findings imply a novel function of ERβ, beyond direct transcriptional control, in regulating DNA methylation at target genes. Further, they shed light on the question how DNA methylation is regulated at specific genomic loci by supporting a concept in which sequence-specific transcription factors can target factors that regulate DNA methylation patterns.

A paradicsomnövények etilén (ET) érzékenységét és ET státusztól függő sóstressz-válaszait kétféle megközelítésben vizsgáltuk. Tanulmányoztuk egyrészt a gyökérközegben, hidropónikus kultúrában alkalmazott exogén 1-aminociklopropán-1-karbonsav (ACC) koncentráció sorozat hatását paradicsomnövények legfontosabb fiziológiai folyamataira, amellyel választ szerettünk volna kapni arra a kérdésre, hogy milyen hatást gyakorol a gyökérközegben, külső tényezők hatására megemelkedett ACC koncentráció azokra a mechanizmusokra, amelyek szerepet játszhatnak az indukált szerzett rezisztenciához hasonlóan egy ezt követő abiotikus stressz akklimatizáció folyamatának gyorsításában.Második kísérlet sorozatunkban vizsgáltuk a szubletális (100 mM) és a letális (250 mM NaCl) sóstressz hatását különböző ET státuszú paradicsomnövények [vad típus (VT), 10 µM ACC-vel előkezelt VT és ET receptor mutáns, Never ripegenotípus] sóstressz akklimatizációban szerepet játszó fiziológiai válaszaiban. Így tanulmányoztuk a vízháztartás, a fotoszintézis, valamint az oxidatív és nitrozatív stresszben szereplő különböző reaktív oxigén- (ROF) és nitrogénformák (RNF) keletkezését, a ROF kioltásában szerepet játszó enzimek aktivitását, valamint a kódoló gének expresszióját a különböző ET státuszú növényekben a sóstressz akklimatizáció során, amellyel választ szerettünk volna kapni arra, hogy mi az ET szerepe a sóstressz-válasz korai időszakában.Fontosabb megfigyeléseinket az 5. melléklet foglalja össze grafikus formában.Eredményeink alapján a következő megállapításokat fogalmaztuk meg:1. A gyökérkezelésként adott ACC többlet egy koncentrációs küszöbértéket meghaladva indukál szignifikáns ET emissziót, ami a gyökerekben nagyobb mértékű, azonban ennek elérése nélkül is fiziológiai válaszokat vált ki.2. A gyökérzónában bekövetkező, nagyon enyhe ACC koncentráció emelkedés (0,01-1 µM) növeli a száraz biomassza gyarapodást a paradicsomnövények hajtásában, nitrozatív stresszt gátló környezetet alakít ki a ROF és RNF molekulák akkumulálódási mintázatában, a gyökércsúcsokban és a levélben egyaránt. Ugyanakkor a magas (100 µM) ACC koncentráció száraztömeg csökkenést, valamint a ROF és RNF felhalmozódását eredményez. Az exogén ACC kezelés tehát növényi szerv és koncentráció-függő módon fokozta a H2O2felhalmozódást, valamint befolyásolta a NO és a ONOOakkumulációs mintázatát. Ugyanakkor a nagy koncentrációjú ACC kezelés sem okozta a növények pusztulását és az enyhe oxidatív stressz kedvező lehet az antioxidáns folyamatok aktiválásának elősegítésében.3. Az exogén ACC jelenléte a gyökérzónában koncentráció és expozíciós idő függvényében serkentheti vagy gátolhatja a fotoszintézist és befolyásolja a két fotokémiai rendszer működését nem öregedő paradicsomlevelekben. Az alacsony 0,01 és 1,0 µM-os ACC koncentrációk a kezelés utáni első két napon serkentőleg hatnak a nettó CO2 fixációra, a 0,01 µM-os ACC szignifikánsan emeli a PSI kvantumhatékonyságát és megváltoztatja a nem fotokémiai kioltási profilját, míg a PSII-re gyakorolt hatása csekély. A 100 µM-os ACC kezelés kifejezetten gátolja a nettó CO2 asszimilációt és a PSII effektív kvantumhatékonyságát, ezzel szemben a PSI kvantumhatásfoka kisebb érzékenységet mutat. Az ACC kezelések – eltérő idő és intenzitásbéli lefolyással – indukálták a fényvédelmi folyamatokat, elsősorban a PSI ciklikus elektronáramlás (CEF-PSI) kapcsolt nem fotokémiai kioltás (NPQ) fokozásán keresztül. 4. A K+ /Na+arányokban a 100 µM ACC kezelés hatására kialakuló csökkenés enyhe sóstressznek tekinthető, ami priming hatású is lehet egy azt követő ozmotikus-/sóstressz akklimatizáció során, ennél fogva az ACC által kiváltott eustresszként definiálható. A 0,01-1,0 µM ACC növeli az oldható cukor és szorbitol tartalmakat, ami szintén hozzájárulhat egy ozmotikus komponenst is tartalmazó abiotikus stressztolerancia kialakításához.

The distribution of sentence length in ordinary language is not well captured by the existing models. Here we survey previous models of sentence length and present our random walk model that offers both a better fit with the data and a better understanding of the distribution. We develop a generalization of KL divergence, discuss measuring the noise inherent in a corpus, and present a hyperparameter-free Bayesian model comparison method that has strong conceptual ties to Minimal Description Length modeling. The models we obtain require only a few dozen bits, orders of magnitude less than the naive nonparametric MDL models would.

There is increasing evidence that endocrine disrupting chemicals (EDCs) are contributing to the rise in metabolic disorders and obesity. Humans are constantly exposed to numerous EDCs, thus human exposure entails complex EDC mixtures. In this study, we examined the effects of an EDC mixture, mixture G, composed of four phthalate esters, triclosan, and three poly- och perfluorinated alkyl substances. Mixture G had previously been defined based on its association with lower birth weight in a pregnancy cohort, where low birth weight is an early risk factor for metabolic morbidities later in life. Here, we studied its effects on adipogenesis and uncovered their underlying transcriptional changes. Human mesenchymal stem cells (hMSCs) were exposed to mixture G in concentrations and mixing ratios that reflect those measured in human serum. Mixture G induced adipogenesis in hMSCs, as evidenced by a dose-dependent increase in lipid droplet accumulation after 14-21 days. Notably, significant adipogenic effects were observed at concentrations comparable to those detected in humans. RNA-sequencing upon exposure for 48 h revealed dose-dependent transcriptional changes in over 1000 genes. Mixture G-induced differentially expressed genes (DEGs) showed significant overlap with genes involved in osteogenesis, with glucocorticoid-regulated genes, and with genes associated with birth weight alterations and diabetes type II. These results indicate that exposure to an environmentally relevant EDC mixture induces adipogenesis and leads to transcriptional alterations that might change the balance between adipogenic and osteogenic differentiation as well as the functionality of MSCs, possibly via interference with glucocorticoid signalling. Thus our findings underscore the role of EDCs as metabolic disruptors and shed light on the molecular mechanisms underlying their potential contribution to the development of metabolic disorders. An endocrine disruptor mixture linked to lower birth weight increases adipogenesis The mixture induced transcriptomic changes at low doses Affected genes are associated with birth weight and diabetes type II

Based on the scientific literature, in particular on studies with NOX4 deficient mice models, it is increasingly clear, that the inhibition of NOX4 is a promising pharmacologic concept for the treatment of oxidative stress-related diseases. At present no specific NOX4 inhibitor is available for biochemical and/or clinical applications. In our work we aimed to identify and develop novel small-molecule inhibitors of NOX4 enzyme based on the widely accepted strategy of rational drug design. • A cellular assay measuring NOX4 mediated H2O2 production was developed and optimized. About 1100 compounds were tested in this assay for NOX4 inhibition in the frame of a medium high throughput screening. • Following the examination of the intracellular localization of the NOX4 enzyme in vascular endothelial (EA.hy926) cells, a broken cell assay was developed to check the specificity of the compounds. In this assay we have determined the IC50 values and excluded the compounds with potential off-target activity. • For the same reason, the selectivity of the molecules was also tested in a NOX2 based cellular assay. As a result of this assay we could identify not only the NOX2 inhibitors (not selective NOX4 inhibitors), but also the ROS scavengers. • The toxicity and antiproliferative effects of the compounds were successfully characterized in three different assays (luminescence cell viability-, MTT- and FACS assay) using two different cell lines (293 FS and EA.hy926). • As a part of early ADME(T) characterization, we also tested the lipophilicity and permeability of the compounds. • Last but not least, applying the physico-chemical properties of the effective NOX4 inhibitor compound families, eventually structure-activity relationship (SAR) model was developed. Based on the SAR model, we could show the possibly beneficial structural properties of a NOX4 inhibitor. As a result of our scientific work, promising NOX4 inhibitory compounds with low micromolar IC50 values were selected. These compounds might help to puzzle out the function of NOX4 enzyme and treat the oxidative stress-mediated diseases.