c-MYC empowers transcription and productive splicing of the oncogenic splicing factor Sam68 in cancer

The splicing factor Sam68 is upregulated in many human cancers, including prostate cancer (PCa) where it promotes cell proliferation and survival. Nevertheless, in spite of its frequent upregulation in cancer, the mechanism(s) underlying its expression are largely unknown. Herein, bioinformatics analyses identified the promoter region of the Sam68 gene (KHDRBS1) and the proto-oncogenic transcription factor c-MYC as a key regulator of Sam68 expression. Upregulation of Sam68 and c-MYC correlate in PCa patients. c-MYC directly binds to and activates the Sam68 promoter. Furthermore, c-MYC affects productive splicing of the nascent Sam68 transcript by modulating the transcriptional elongation rate within the gene. Importantly, c-MYC-dependent expression of Sam68 is under the tight control of external cues, such as androgens and/or mitogens. These findings uncover an unexpected coordination of transcription and splicing of Sam68 by c-MYC, which may represent a key step in PCa tumorigenesis

Evolution and architecture of a West Mediterranean Upper Pleistocene to Holocene coastal apron-fan system

The Quaternary deposits of tectonically stable areas are a powerful tool to investigate high-frequency climate variations (<10 ka) and to distinguish allogenic and autogenic factors controlling deposition. Therefore, an Upper Pleistocene—Holocene coastal apron-fan system in north—western Sardinia (Porto Palmas, Italy) was studied to investigate the relations between climate changes, sea-level fluctuations and sediment source-supply that controlled its development. The sedimentary sequence records the strong influence of local (wet/dry) and worldwide (sea-level) environmental variations in the sedimentation and preservation of the deposits. A multi-disciplinary approach allowed subdivision of the succession into four major, unconformity-bounded stratigraphic units: U1 U2, U3 and U4. Unit U1, tentatively dated to the warm and humid Marine Isotopic Stage (MIS) 5, consists of sandy, gravelly coastal/beach deposits developed during high sea-level in low-lying areas. Unit U2 consists of debris-flow dominated fan-deposits (ca 74 ka; MIS 4), preserved as partial fills of small valleys and coves. Unit U2 is mainly composed of reddish silty conglomerate to pebbly siltstones sourced from the Palaeozoic metamorphic inland hills (bedrock), superficially disintegrated during the preceding warm, vegetation-rich MIS 5. The cold and semi-arid climate strongly reduced vegetation cover along the valley flanks. Therefore, sediment gravity-flow processes, possibly activated by rainstorms, led to deposition of debris-flow dominated fans. Unit U3 consists of water-flow dominated alluvial-fan deposits (ca 47 to 23 ka; MIS 3), developed on a slightly inclined coastal plain. Unit U3 is composed of sandstone and sandy conglomerate fed from two main sediment sources: metamorphic inland bedrock and Quaternary bioclastic-rich shelf-derived sands. During this cold phase, sea-level dropped sufficiently to expose bioclastic sands accumulated on the shelf. Frequent climate fluctuations favoured inland aeolian transport of sand during dry phases, followed by reworking of the aeolian bodies by flash floods during wet phases. Bedrock-derived fragments mixed with water-reworked, wind-blown sands led to the development of water-flow dominated fans. The Dansgaard—Oeschger events possibly associated with sand landward deflation and main fan formations are Dansgaard—Oeschger 13 (ca 47 ka), Dansgaard—Oeschger 8 (ca 39 ka) and Dansgaard—Oeschger 2 (ca 23 ka). No record of sedimentation during MIS 2 was observed. Finally, bioclastic-rich aeolianites (Unit U4, ca 10 to 5 ka; MIS 1), preserved on a coastal slope, were developed during the Holocene transgression (ca 10 to 5 ka; MIS 1). The studied sequence shows strong similarities with those of other Mediterranean sites; it is, however, one of the few where the main MIS 4 and MIS 3 climatic fluctuations are registered in the sedimentary record

Effectiveness of a new toothbrush design versus a conventional tongue scraper in improving breath odor and reducing tongue microbiota

For centuries, specific instruments or regular toothbrushes have routinely been used to remove tongue biofilm and improve breath odor. Toothbrushes with a tongue scraper on the back of their head have recently been introduced to the market. The present study compared the effectiveness of a manual toothbrush with this new design, i.e., possessing a tongue scraper, and a commercial tongue scraper in improving breath odor and reducing the aerobic and anaerobic microbiota of tongue surface. The evaluations occurred at 4 moments, when the participants (n=30) had their halitosis quantified with a halimeter and scored according to a 4-point scoring system corresponding to different levels of intensity. Saliva was collected for counts of aerobic and anaerobic microorganisms. Data were analyzed statistically by Friedman's test (p<0.05). When differences were detected, the Wilcoxon test adjusted for Bonferroni correction was used for multiple comparisons (group to group). The results confirmed the importance of mechanical cleaning of the tongue, since this procedure provided an improvement in halitosis and reduction of aerobe and anaerobe counts. Regarding the evaluated methods, the toothbrush's tongue scraper and conventional tongue scraper had a similar performance in terms of breath improvement and reduction of tongue microbiota, and may be indicated as effective methods for tongue cleaning

CDK12/13 promote splicing of proximal introns by enhancing the interaction between RNA polymerase II and the splicing factor SF3B1

Transcription-associated cyclin-dependent kinases (CDKs) regulate the transcription cycle through sequential phosphorylation of RNA polymerase II (RNAPII). Herein, we report that dual inhibition of the highly homologous CDK12 and CDK13 impairs splicing of a subset of promoter-proximal introns characterized by weak 3 ' splice sites located at larger distance from the branchpoint. Nascent transcript analysis indicated that these introns are selectively retained upon pharmacological inhibition of CDK12/13 with respect to downstream introns of the same pre-mRNAs. Retention of these introns was also triggered by pladienolide B (PdB), an inhibitor of the U2 small nucelar ribonucleoprotein (snRNP) factor SF3B1 that recognizes the branchpoint. CDK12/13 activity promotes the interaction of SF3B1 with RNAPII phosphorylated on Ser2, and disruption of this interaction by treatment with the CDK12/13 inhibitor THZ531 impairs the association of SF3B1 with chromatin and its recruitment to the 3 ' splice site of these introns. Furthermore, by using suboptimal doses of THZ531 and PdB, we describe a synergic effect of these inhibitors on intron retention, cell cycle progression and cancer cell survival. These findings uncover a mechanism by which CDK12/13 couple RNA transcription and processing, and suggest that combined inhibition of these kinases and the spliceosome represents an exploitable anticancer approach

Adaptive design of experiments for efficient and accurate estimation of aerodynamic loads

Aerodynamic design, which aims at developing the outer shape of the aircraft while meeting several contrasting requirements, demands an accurate and reliable aerodynamic database. Computing forces and moments with the highest level of ?fidelity is a prerequisite, but practically limited by wall clock time and available computing resources. An e?fficient and robust approach is therefore sought after. This study investigates two design of experiments algorithms in combination with surrogate modelling. In traditional design of experiments, the samples are selected a priori before running the numerical explorative campaign. It is well-?known that this may result in either poor prediction capabilities or high computational costs. The second strategy employs an adaptive design of experiments algorithm. As opposed to the former, this is a self?-learning technique that iteratively: i) identi?fies the regions of the design space that are characterised by stronger non?linearities; and ii) select the new samples in order to maximise the information contentassociated with the simulations to be performed during the next iteration. In this work, the Reynolds?-averaged Navier-?Stokes equations are solved around a complete aircraft confi?guration. A representative ?flight envelope is created taking the angle of attack and Mach number as design parameters. The adaptive strategy is found to perform better than the traditional counterpart. This is quantifi?ed in terms of the sum of the squared error between the surrogate model predictions and CFD results. For the pitch moment coe?fficient, which shows strong non?linearities, the error metric using the adaptive strategy is reduced by about one order of magnitude compared to the traditional approach. Furthermore, the proposed adaptive methodology, which is employed on a high performance computing facility, requires no extra costs or complications than a traditional methodolog

Evolution and architecture of a West Mediterranean upper Pleistocene to Holocene coastal apron-fan system

The Quaternary deposits of tectonically stable areas are a powerful tool to investigate high-frequency climate variations (&#60;10 ka) and to distinguish allogenic and autogenic factors controlling deposition. Therefore, an Upper Pleistocene&#8212;Holocene coastal apron-fan system in north&#8212;western Sardinia (Porto Palmas, Italy) was studied to investigate the relations between climate changes, sea-level fluctuations and sediment source-supply that controlled its development. The sedimentary sequence records the strong influence of local (wet/dry) and worldwide (sea-level) environmental variations in the sedimentation and preservation of the deposits. A multi-disciplinary approach allowed subdivision of the succession into four major, unconformity-bounded stratigraphic units: U1 U2, U3 and U4. Unit U1, tentatively dated to the warm and humid Marine Isotopic Stage (MIS) 5, consists of sandy, gravelly coastal/beach deposits developed during high sea-level in low-lying areas. Unit U2 consists of debris-flow dominated fan-deposits (ca 74 ka; MIS 4), preserved as partial fills of small valleys and coves. Unit U2 is mainly composed of reddish silty conglomerate to pebbly siltstones sourced from the Palaeozoic metamorphic inland hills (bedrock), superficially disintegrated during the preceding warm, vegetation-rich MIS 5. The cold and semi-arid climate strongly reduced vegetation cover along the valley flanks. Therefore, sediment gravity-flow processes, possibly activated by rainstorms, led to deposition of debris-flow dominated fans. Unit U3 consists of water-flow dominated alluvial-fan deposits (ca 47 to 23 ka; MIS 3), developed on a slightly inclined coastal plain. Unit U3 is composed of sandstone and sandy conglomerate fed from two main sediment sources: metamorphic inland bedrock and Quaternary bioclastic-rich shelf-derived sands. During this cold phase, sea-level dropped sufficiently to expose bioclastic sands accumulated on the shelf. Frequent climate fluctuations favoured inland aeolian transport of sand during dry phases, followed by reworking of the aeolian bodies by flash floods during wet phases. Bedrock-derived fragments mixed with water-reworked, wind-blown sands led to the development of water-flow dominated fans. The Dansgaard&#8212;Oeschger events possibly associated with sand landward deflation and main fan formations are Dansgaard&#8212;Oeschger 13 (ca 47 ka), Dansgaard&#8212;Oeschger 8 (ca 39 ka) and Dansgaard&#8212;Oeschger 2 (ca 23 ka). No record of sedimentation during MIS 2 was observed. Finally, bioclastic-rich aeolianites (Unit U4, ca 10 to 5 ka; MIS 1), preserved on a coastal slope, were developed during the Holocene transgression (ca 10 to 5 ka; MIS 1). The studied sequence shows strong similarities with those of other Mediterranean sites; it is, however, one of the few where the main MIS 4 and MIS 3 climatic fluctuations are registered in the sedimentary record

Transcatheter embolization with Squid, combined with other embolic agents or alone, in different abdominal diseases: a single-center experience in 30 patients

BACKGROUND: Squid, as Onyx, is an ethylene-vinyl alcohol copolymer (EVOH)-based liquid embolic agent developed for neuroradiologic interventions with poor application in abdominal district. Our aim was to evaluate safety, complications, and efficacy of transcatheter embolization using the two available formulations Squid-18 and 12, in 30 patients affected by different abdominal diseases.RESULTS: Transcatheter embolization with Squid, combined with other embolic agents, as poly vinyl alcohol (PVA) particles, coils and amplatzer plugs, or alone (type 2 endoleak), was performed in 30 patients, as follows: 10 portal vein embolizations (PVEs), 6 arteriovenous malformations (AVMs), 5 visceral artery aneurysms (VAAs), 4 type 2 endoleaks, 3 preoperative embolizations, 1 acute arterial bleeding, 1 female varicocele. Squid was always administered using dimethyl sulfoxide (DMSO) compatible microcatheters. Technical success, 30-day clinical success and complications were assessed. Technical success was 90%. 3 patients (2 AVMs, 1 VAA) required re-intervention successfully performed in all cases. Major complications, cases of microcatheter entrapment and DMSO-related poor pain control were not recorded. 30-day clinical success was 93.3%: in 2 patients submitted to PVE a sufficient future liver remnant (FLR) hypertrophy was not achieved.CONCLUSION: Squid was successfully used with low complication rate in many abdominal diseases showing a valid embolic action either combined with other embolic agents or alone in type 2 endoleak. The availability of different formulations (Squid-18 and Squid-12) variable for viscosity makes Squid preferable to Onyx as EVOH-based liquid embolic agent, even though comparable studies in different abdominal districts with a larger cohort of patients will be necessary

Unraveling the degradation mechanism in FIrpic based Blue OLEDs: II. Trap and detect molecules at the interfaces

The impact of organic light emitting diodes (OLEDs) in modern life is witnessed by their wide employment in full-color, energy-saving, flat panel displays and smart-screens; a bright future is likewise expected in the field of solid state lighting. Cyclometalated iridium complexes are the most used phosphorescent emitters in OLEDs due to their widely tunable photophysical properties and their versatile synthesis. Blue-emitting OLEDs, suffer from intrinsic instability issues hampering their long term stability. Backed by computational studies, in this work we studied the sky-blue emitter FIrpic in both ex-situ and in-situ degradation experiments combining complementary, mutually independent, experiments including chemical metathesis reactions, in liquid phase and solid state, thermal and spectroscopic studies and LC-MS investigations. We developed a straightforward protocol to evaluate the degradation pathways in iridium complexes, finding that FIrpic degrades through the loss of the picolinate ancillary ligand. The resulting iridium fragment was than efficiently trapped "in-situ" as BPhen derivative 1. This process is found to be well mirrored when a suitably engineered, FIrpic-based, OLED is operated and aged. In this paper we (i) describe how it is possible to effectively study OLED materials with a small set of readily accessible experiments and (ii) evidence the central role of host matrix in trapping experiments.Comment: 13 pages, 6 figure