Orphan nuclear receptor Nurr1 induces neuron differentiation from embryonic cortical precursor cells via an extrinsic paracrine mechanism

AbstractNurr1 is an orphan nuclear receptor-type transcription factor (TF) that plays critical roles in midbrain dopamine neuron development. This study demonstrated a novel role for Nurr1 in neuronal/astrocytic differentiation of neural precursor (NP) cells isolated from rat embryonic cortices: overexpression of this TF promoted NP cell differentiation towards neurons at the expense of astrocytic differentiation. Single cell-based lineage analyses and experiments using co-cultures revealed that Nurr1 elicited its neurogenic role in an extrinsic paracrine manner. We defined diffusible factors and downstream neurogenic TFs responsible for the Nurr1-mediated neuronal differentiation

Učinci prenatalne i postnatalne izloženosti perfluorooktanskoj kiselini na ekspresiju glavnih gena povezanih s reprodukcijom u mišjem hipotalamusu i spolnim žlijezdama

Perfluorooctanoic acid (PFOA), a ubiquitous environmental pollutant reported to be an endocrine disruptor, is used in many industrial and consumer products. Although the adverse effects of PFOA on the reproductive health of animals and humans have been widely reported, most studies have focused on assessing the anatomical features and conventional histology of adult gonads. Therefore, the molecular mechanisms activated in the hypothalamus and gonads following PFOA exposure during the pre- and postnatal periods are not clear. This study used a mouse model to evaluate the effects of PFOA exposure on the alteration of molecular mechanisms in the hypothalamus and gonads during the prenatal and postpartum periods. Changes in gene and protein expression following PFOA exposure were evaluated by quantitative polymerase chain reaction and Western blotting, respectively. Kisspeptin 1 and gonadotropin-releasing hormone expression in the hypothalamus of female and male mouse pups was significantly decreased. Additionally, Cyp17a1 expression was upregulated in male offspring testes, while Cyp17a1 and Cyp19a1 expression was downregulated in female offspring ovaries. Changes at the molecular level due to PFOA exposure in the early stages of development did not show sex-related differences in the hypothalamus; however, such differences were confirmed in the gonads. These results could be used as basic data to study the molecular mechanisms underlying the reproductive dysfunction caused by PFOA exposure in the early stages of embryonic development.Perfluorooktanska kiselina (PFOA) sveprisutna je onečišćujuća tvar za okoliš, za koju je zabilježeno da uzrokuje i endokrinopatije, a upotrebljava se u mnogim industrijskim proizvodima. Bez obzira na poznate i zabilježene nuspojave PFOA-e na reproduktivno zdravlje životinja i ljudi, većina se istraživanja usredotočuje na procjenu anatomskih histoloških značajki u spolnim žlijezdama odraslih jedinki. Molekularni mehanizmi koji se aktiviraju u hipotalamusu i spolnim žlijezdama nakon izlaganja PFOA-i stoga nisu razjašnjeni. U ovom je istraživanju upotrijebljen mišji model za procjenu učinaka izlaganja PFOA-i na promjenu molekularnih mehanizama u hipotalamusu i spolnim žlijezdama za vrijeme prijeporođajnog i poslijeporođajnog razdoblja. Promjene u ekspresiji gena i proteina nakon izloženosti PFOA-i analizirane su kvantitativnom PCR metodom i metodom Western blotting. Ekspresija kispeptina 1 i hormona koji oslobađa gonadotropin u hipotalamusu ženske i muške mladunčadi bila je znakovito smanjena. Osim toga ekpresija Cyp17a1 bila je pojačana u testisima muških potomaka, dok je ekspresija Cyp17a1 i Cyp19a1 u jajnicima ženskih potomaka bila smanjena. Kod promjena na molekularnoj razini u hipotalamusu u ranim razvojnim stadijima nije bilo razlike među spolovima, dok je kod promjena u spolnim žlijezdama povrđena razlika među spolovima. Rezultati ovog istraživanja mogli bi biti korisni kao osnovni podaci u proučavanju molekularnih mehanizama podležeće reproduktivne disfunkcije uzrokovane izloženošću PFOA-i u ranim stadijima embrionalnog razvoja

A new multiple flights routing and scheduling algorithm in terminal manoeuvring area

We address multiple flights planning problems from its initial waypoint to its destination while satisfying the minimum separation requirement between each aircraft at all times in a Terminal Manoeuvring Area (TMA) to maintain or increase runway throughput. Due to operational constraints for safety, most of the current aircraft fly over or by waypoints, and along nominal routes in the airspace. Where the waypoints and routes in the airspace can be modelled as a weighted digraph, called airspace graph. We propose a problem that consists of determining a flight path (routing problem) and its speed profile (scheduling problem) in a given airspace graph in which a time-based weighting scheme of the airspace graph is proposed to reflect a speed-limitation-compliant schedule that satisfy the minimum separation requirement. For multiple flights cases, the flight paths and schedules are obtained by iteratively solving the problem for each flight by applying the First Come First Served (FCFS) algorithm to determine an arrival sequence. The main contributions of this paper are increasing a solution search space by solving two problems simultaneously, efficient computational time, and providing the separation-compliant flight path and speed profile within the speed limitation for each flight. We demonstrate the advantages of the proposed approach through a case study in which multiple flights arrive at a single airport, and we compare the results with Regulated Tactical Flight Model (RTFM) obtained from EUROCONTROL Demand Data Repository 2 (DDR2). Although, we consider only a single airport and make an assumption to simplify flight routes from holding stacks to a Final Approach Fix (FAF), the results show the potential usage of the proposed algorithm as a Decision Support Tool (DST) for Air Traffic Controllers (ATCOs) if the following considerations are taken into account: detailed routes-based flights after the holding stacks, multiple airports, departing aircraft, all possibe aircraft types, and uncertainties produced by external sources

Epigenetic toxicity and cytotoxicity of perfluorooctanoic acid and its effects on gene expression in embryonic mouse hypothalamus cells

Premda je perfluorooktanska kiselina (PFOA) dobro znana kao endokrini disruptor, i dalje se malo zna o mehanizmima u pozadini njezina djelovanja na stanice i njezine toksičnosti u kritičnoj fazi razvoja hipotalamusa. Stoga smo istražili njezino djelovanje u staničnoj liniji N46 hipotalamusa mišjeg embrija (mHypoE-N46) da bismo saznali o mehanizmima kroz koje ih PFOA oštećuje. S tom smo svrhom analizirali vijabilnost stanica, globalnu metilaciju DNA i gensku ekspresiju izloženih stanica. Porastom koncentracija PFOA padala je stanična vijabilnost, a globalna DNA metilacija rasla. Usto je PFOA značajno utjecala na ekspresiju gena povezanih s apoptozom i staničnim ciklusom, neurotrofnih gena te Tet, Dnmt i Mecp2 gena. Naše istraživanje ukazuje na to da izloženost PFOA utječe na preživljenje stanica hipotalamusa mišjeg embrija reprogramiranjem obrazaca metilacije DNA te promjenama u genima zaduženim za održavanje homeostaze. Metilacija DNA i promjene u ekspresiji Mecp2 gena izazvane djelovanjem PFOA također imaju široki spektar implikacija, budući da utječu na promjene u genima zaduženim za druge važne mehanizme u embrijskom hipotalamusu. Stoga naše istraživanje može poslužiti kao dobra polazna točka za daljnje istraživanje mehanizama djelovanja PFOA na razvoj hipotalamusa.Even though the endocrine-disrupting potential of perfluorooctanoic acid (PFOA) is well known, the mechanisms underlying its cellular and epigenetic toxicity at the critical stage of hypothalamic development are poorly understood. This is why we studied its effects on the embryonic mouse hypothalamic cell line N46 (mHypoE-N46) with a hope to shed more light on the mechanisms through which PFOA causes embryonic hypothalamic cell damage. To do that, we studied cell viability, global DNA methylation, and gene expression in cells exposed to PFOA. As the PFOA dose increased, cell viability decreased, while global DNA methylation increased. PFOA also significantly altered the expression of genes related to the apoptosis and cell cycle, neurotrophic genes, and the Tet, Dnmt, and Mecp2 genes. Our findings suggest that exposure to PFOA affects cell survival through the reprogramming of embryonic hypothalamic DNA methylation patterns and altering cell homeostasis genes. DNA methylation and changes in the Mecp2 gene expression induced by PFOA also imply wider ramifications, as they alter genes of other major mechanisms of the embryonic hypothalamus. Our study may therefore serve as a good starting point for further research into the mechanisms of PFOA effect of hypothalamic development

Laparoscopic Surgical Management and Clinical Characteristics of Ovarian Fibromas

Ovarian fibromas may be misdiagnosed as uterine myoma or ovarian malignant tumor. Laparoscopic examination appears to be an effective and safe surgical approach for managing ovarian fibromas