The human nuclear exosome targeting complex is loaded onto newly synthesized RNA to direct early ribonucleolysis

SummaryThe RNA exosome complex constitutes the major nuclear eukaryotic 3′-5′ exonuclease. Outside of nucleoli, the human nucleoplasmic exosome is directed to some of its substrates by the nuclear exosome targeting (NEXT) complex. How NEXT targets RNA has remained elusive. Using an in vivo crosslinking approach, we report global RNA binding sites of RBM7, a key component of NEXT. RBM7 associates broadly with RNA polymerase II-derived RNA, including pre-mRNA and short-lived exosome substrates such as promoter upstream transcripts (PROMPTs), enhancer RNAs (eRNAs), and 3′-extended products from snRNA and replication-dependent histone genes. Within pre-mRNA, RBM7 accumulates at the 3′ ends of introns, and pulse-labeling experiments demonstrate that RBM7/NEXT defines an early exosome-targeting pathway for 3′-extended snoRNAs derived from such introns. We propose that RBM7 is generally loaded onto newly synthesized RNA to accommodate exosome action in case of available unprotected RNA 3′ ends

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Experimental Small Bowel Transplantation

The small bowel transplantation (SBT) represents reasonable alternative to ultimate total parenteral nutrition of the patient suffering from terminal stage of chronic bowel failure. To date, the small bowel transplantation was not carried out in the Czech Republic. The initial experimental research and gaining experience with transplantations on animal models are inevitable before successful commencement of small bowel transplantation programme. In my dissertation thesis I am in full details describing the surgical technique of small bowel transplantation in rat. In comparison with the published data I have succeed to reach rather similar results of operating time and survival of the experimental animals. In the second part of my experiment I tried to influence the acute rejection of the small bowel graft occurrence by administration of cytostatic agent gemcitabin. The chosen dosage of the remedy did not suppress the rejection. In the third part I am describing the surgical technique of lymphatic vessels reconstruction in SBT rat model, which might lead to improvement of the SBT outcome. The last part of my dissertation thesis is preclinical. I am describing the initial experience with surgical technique of small bowel graft harvesting from cadaverous donor

4D Doppler Ultrasound in High Grade Serous Ovarian Cancer Vascularity Evaluation—Preliminary Study

The aim of the study was to evaluate the usefulness of 4D Power Doppler tissue evaluation to discriminate between normal ovaries and ovarian cancer tumors. This was a prospective observational study. Twenty-three cases of surgically confirmed ovarian High Grade Serous Carcinoma (HGSC) were analyzed. The control group consisted of 23 healthy patients, each matching their study-group counterpart age wise (±3 years) and according to their menopausal status. Transvaginal Doppler 4D ultrasound scans were done on every patient and analyzed with 3D/4D software. Two 4D indices—volumetric Systolic/Diastolic Index (vS/D) and volumetric Pulsatility Index (vPI)—were calculated. To keep results standardized and due to technical limitations, virtual 1cc spherical tissue samples taken from the part with highest vascularization as detected by bi-directional Power Doppler were analyzed for both groups of ovaries. Values of volumetric S/D indices and volumetric PI indices were statistically lower in ovarian malignant tumors compared to normal ovaries: 1.096 vs. 1.794 and 0.092 vs. 0.558, respectively (p < 0.001). The 4D bi-directional Power Doppler vascular indices were statistically different between malignant tumors and normal ovaries. These findings could support the rationale for future studies for assessing this technology to discriminate between malignant and benign tumors

Glucocorticoid receptor signaling in astrocytes is required for aversive memory formation

Abstract Stress elicits the release of glucocorticoids (GCs) that regulate energy metabolism and play a role in emotional memory. Astrocytes express glucocorticoid receptors (GR), but their contribution to cognitive effects of GC’s action in the brain is unknown. To address this question, we studied how astrocyte-specific elimination of GR affects animal behavior known to be regulated by stress. Mice with astrocyte-specific ablation of GR presented impaired aversive memory expression in two different paradigms of Pavlovian learning: contextual fear conditioning and conditioned place aversion. These mice also displayed compromised regulation of genes encoding key elements of the glucose metabolism pathway upon GR stimulation. In particular, we identified that the glial, but not the neuronal isoform of a crucial stress-response molecule, Sgk1, undergoes GR-dependent regulation in vivo and demonstrated the involvement of SGK1 in regulation of glucose uptake in astrocytes. Together, our results reveal astrocytes as a central element in GC-dependent formation of aversive memory and suggest their relevance for stress-induced alteration of brain glucose metabolism. Consequently, astrocytes should be considered as a cellular target of therapies of stress-induced brain diseases