mTOR Controls Ovarian Follicle Growth by Regulating Granulosa Cell Proliferation

We have shown that inhibition of mTOR in granulosa cells and ovarian follicles results in compromised granulosa proliferation and reduced follicle growth. Further analysis here using spontaneously immortalized rat granulosa cells has revealed that mTOR pathway activity is enhanced during M-phase of the cell cycle. mTOR specific phosphorylation of p70S6 kinase and 4E-BP, and expression of Raptor are all enhanced during M-phase. The predominant effect of mTOR inhibition by the specific inhibitor Rapamycin (RAP) was a dose-responsive arrest in the G1 cell cycle stage. The fraction of granulosa cells that continued to divide in the presence of RAP exhibited a dose-dependent increase in aberrant mitotic figures known as anaphase bridges. Strikingly, estradiol consistently decreased the incidence of aberrant mitotic figures. In mice treated with RAP, the mitotic index was reduced compared to controls, and a similar increase in aberrant mitotic events was noted. RAP injected during a superovulation regime resulted in a dose-dependent reduction in the numbers of eggs ovulated. Implications for the real-time regulation of follicle growth and dominance, including the consequences of increased numbers of aneuploid granulosa cells, are discussed

Enhancement of the activity of phenoxodiol by cisplatin in prostate cancer cells

Phenoxodiol is a novel isoflav-3-ene, currently undergoing clinical trials, that has a broad in vitro activity against a number of human cancer cell lines. Phenoxodiol alone inhibited DU145 and PC3 in a dose- and time-dependent manner with IC50 values of 8±1 and 38±9 μM, respectively. The combination of phenoxodiol and cisplatin was synergistic in DU145, and additive in PC3, as assessed by the Chou–Talalay method. Carboplatin was also synergistic in combination with phenoxodiol in DU145 cells. The activity of the phenoxodiol and cisplatin combination was confirmed in vivo using a DU145 xenograft model in nude mice. Pharmacokinetic data from these mice suggest that the mechanism of synergy may occur through a pharmacodynamic mechanism. An intracellular cisplatin accumulation assay showed a 35% (P<0.05) increase in the uptake of cisplatin when it was combined in a ratio of 1 μM: 5 μM phenoxodiol, resulting in a 300% (P<0.05) increase in DNA adducts. Taken together, our results suggest that phenoxodiol has interesting properties that make combination therapy with cisplatin or carboplatin appealing

Coxiella burnetii, the Agent of Q Fever, Replicates within Trophoblasts and Induces a Unique Transcriptional Response

Q fever is a zoonosis caused by Coxiella burnetii, an obligate intracellular bacterium typically found in myeloid cells. The infection is a source of severe obstetrical complications in humans and cattle and can undergo chronic evolution in a minority of pregnant women. Because C. burnetii is found in the placentas of aborted fetuses, we investigated the possibility that it could infect trophoblasts. Here, we show that C. burnetii infected and replicated in BeWo trophoblasts within phagolysosomes. Using pangenomic microarrays, we found that C. burnetii induced a specific transcriptomic program. This program was associated with the modulation of inflammatory responses that were shared with inflammatory agonists, such as TNF, and more specific responses involving genes related to pregnancy development, including EGR-1 and NDGR1. In addition, C. burnetii stimulated gene networks organized around the IL-6 and IL-13 pathways, which both modulate STAT3. Taken together, these results revealed that trophoblasts represent a protective niche for C. burnetii. The activation program induced by C. burnetii in trophoblasts may allow bacterial replication but seems unable to interfere with the development of normal pregnancy. Such pathophysiologocal processes should require the activation of immune placental cells associated with trophoblasts

Admixture Fine-Mapping in African Americans Implicates XAF1 as a Possible Sarcoidosis Risk Gene

Sarcoidosis is a complex, multi-organ granulomatous disease with a likely genetic component. West African ancestry confers a higher risk for sarcoidosis than European ancestry. Admixture mapping provides the most direct method to locate genes that underlie such ethnic variation in disease risk. We sought to identify genetic risk variants within four previously-identified ancestry-associated regions-6p24.3-p12.1, 17p13.3-13.1, 2p13.3-q12.1, and 6q23.3-q25.2-in a sample of 2,727 African Americans. We used logistic regression fit by generalized estimating equations and the MIX score statistic to determine which variants within ancestry-associated regions were associated with risk and responsible for the admixture signal. Fine mapping was performed by imputation, based on a previous genome-wide association study; significant variants were validated by direct genotyping. Within the 6p24.3-p12.1 locus, the most significant ancestry-adjusted SNP was rs74318745 (p = 9.4*10-11), an intronic SNP within the HLA-DRA gene that did not solely explain the admixture signal, indicating the presence of more than a single risk variant within this well-established sarcoidosis risk region. The locus on chromosome 17p13.3-13.1 revealed a novel sarcoidosis risk SNP, rs6502976 (p = 9.5*10-6), within intron 5 of the gene X-linked Inhibitor of Apoptosis Associated Factor 1 (XAF1) that accounted for the majority of the admixture linkage signal. Immunohistochemical expression studies demonstrated lack of expression of XAF1 and a corresponding high level of expression of its downstream target, X-linked Inhibitor of Apoptosis (XIAP) in sarcoidosis granulomas. In conclusion, ancestry and association fine mapping revealed a novel sarcoidosis susceptibility gene, XAF1, which has not been identified by previous genome-wide association studies. Based on the known biology of the XIAP/XAF1 apoptosis pathway and the differential expression patterns of XAF1 and XIAP in sarcoidosis granulomas, we suggest that this pathway may play a role in the maintenance of sarcoidosis granulomas

Assessment of comfort traveling in buses public transport

W artykule przedstawiono wyniki badań przeprowadzonych przez autorów w kołowych pojazdach komunikacji miejskiej. Opisano przyczyny powstawania drgań w autobusach oraz zagrożenia wynikające z narażenia organizmu człowieka na ich ekspozycję. Przedstawiono rozwiązania konstrukcyjne stosowane w autobusach miejskich oraz dokonano analizy wpływu poszczególnych elementów na drgania występujące w przestrzeni transportowej pojazdu. Obiektami badań były autobusy Przedsiębiorstwa Komunikacji Miejskiej Sosnowiec, w których prowadzono badania w warunkach normalnej eksploatacji. Przeprowadzone wnioskowanie pozwoliło na ocenę komfortu podróżowania na wybranych miejscach pasażerskich, rozmieszczonych równomiernie w całym pojeździe.The article presents the results of research conducted by the authors of wheeled transport vehicles. Described the causes of vibration in the buses and the risks resulting from exposure of the human body on their exposure. Presented construction solutions used in city buses and an analysis of the impact of individual components for vibration occurring in passenger space. Research facilities were buses from Sosnowiec Public Transport Company in which the study was conducted in normal transport operation. Carried out to assess the inference allowed the comfort of traveling on selected passenger seats, evenly distributed throughout the vehicle

Tram tracks design codes and contemporary trams

Projektowanie tras tramwajowych w polskich miastach odbywa się na podstawie starych aktów prawnych, a nieliczne nowe zapisy w innych aktach prawnych nie uwzględniają wystarczająco specyfiki ruchu tramwajowego. Zmiany są potrzebne gdyż od czasu napisania szczegółowych wytycznych nastąpiła zdecydowana wymiana taboru tramwajowego, zmieniły się uwarunkowania społeczne i urbanistyczne. Tramwaje muszą być konkurencyjne wobec ruchu samochodowego, a jednocześnie spełniać zwiększone wymogi ekologiczne. Obecne nieaktualne przepisy prowadzą w najlepszym razie do podejmowania nieoptymalnych decyzji, w skrajnych zaś przypadkach były jedną z przyczyn wypadków tramwajowych. Konieczne jest więc opracowanie nowych szczegółowych wytycznych i systemowa weryfikacja aktów prawnych pod kątem uwzględniania specyfiki tras tramwajowych.Design of tram tracks in Polish cities is based on old regulations, with some new codes failing to include a specific character of tram traffic. New regulations are necessary, because from the time the old regulations were written, the rolling stock has changed significantly. Social, urban and environmental requirements have also changed, and the tram is now required to be competitive to car traffic. Using old codes in this new situation results at best in choosing non-optimal solutions, at worst causing tram crashes. There is therefore a need for writing new detailed rules for designing tram tracks and for a verification of the legal system how it includes the specific character of tram traffic