Coordinating DNA Replication and Mitosis through Ubiquitin/SUMO and CDK1

Post-translational modification of the DNA replication machinery by ubiquitin and SUMO plays key roles in the faithful duplication of the genetic information. Among other functions, ubiquitination and SUMOylation serve as signals for the extraction of factors from chromatin by the AAA ATPase VCP. In addition to the regulation of DNA replication initiation and elongation, we now know that ubiquitination mediates the disassembly of the replisome after DNA replication termination, a process that is essential to preserve genomic stability. Here, we review the recent evidence showing how active DNA replication restricts replisome ubiquitination to prevent the premature disassembly of the DNA replication machinery. Ubiquitination also mediates the removal of the replisome to allow DNA repair. Further, we discuss the interplay between ubiquitin-mediated replisome disassembly and the activation of CDK1 that is required to set up the transition from the S phase to mitosis. We propose the existence of a ubiquitin–CDK1 relay, where the disassembly of terminated replisomes increases CDK1 activity that, in turn, favors the ubiquitination and disassembly of more replisomes. This model has important implications for the mechanism of action of cancer therapies that induce the untimely activation of CDK1, thereby triggering premature replisome disassembly and DNA damage.     

Percutaneous Coronary Intervention (PCI) Reprograms Circulating Extracellular Vesicles from ACS Patients Impairing Their Cardio-Protective Properties

Extracellular vesicles (EVs) are promising therapeutic tools in the treatment of cardiovascular disorders. We have recently shown that EVs from patients with Acute Coronary Syndrome (ACS) undergoing sham pre-conditioning, before percutaneous coronary intervention (PCI) were cardio-protective, while EVs from patients experiencing remote ischemic pre-conditioning (RIPC) failed to induce protection against ischemia/reperfusion Injury (IRI). No data on EVs from ACS patients recovered after PCI are currently available. Therefore, we herein investigated the cardio-protective properties of EVs, collected after PCI from the same patients. EVs recovered from 30 patients randomly assigned (1:1) to RIPC (EV-RIPC) or sham procedures (EV-naive) ({"type":"clinical-trial","attrs":{"text":"NCT02195726","term_id":"NCT02195726"}}NCT02195726) were characterized by TEM, FACS and Western blot analysis and evaluated for their mRNA content. The impact of EVs on hypoxia/reoxygenation damage and IRI, as well as the cardio-protective signaling pathways, were investigated in vitro (HMEC-1 + H9c2 co-culture) and ex vivo (isolated rat heart). Both EV-naive and EV-RIPC failed to drive cardio-protection both in vitro and ex vivo. Consistently, EV treatment failed to activate the canonical cardio-protective pathways. Specifically, PCI reduced the EV-naive Dusp6 mRNA content, found to be crucial for their cardio-protective action, and upregulated some stress- and cell-cycle-related genes in EV-RIPC. We provide the first evidence that in ACS patients, PCI reprograms the EV cargo, impairing EV-naive cardio-protective properties without improving EV-RIPC functional capability.     

BRAF Gene and Melanoma: Back to the Future

As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.     

Calcium aluminate cement in castable alumina: From hydrate bonding to the in situ formation of calcium hexaluminate

Calcium hexaluminate (CA₆) is an intrinsically densification-resistant material, therefore, its porous structures are key materials for applications as high-temperature thermal insulators. This article reports on the combination of calcined alumina and calcium aluminate cement (CAC) in castable aqueous suspensions for the in situ production of porous CA₆. The CAC content (10–34 vol%) and the curing conditions ensure structural integrity prior to sintering and maximize the development of hydrated phases. Changes in physical properties, crystalline phases, and microstructure were investigated after isothermal treatments (120–1500 °C), and three sequential porogenic events were observed. The hydration of CAC preserved the water-derived pores (up to 120 °C), and the dehydroxylation of CAC hydrates (250–700 °C) generated inter-particles pores. Moreover, the in situ expansive formation of CA₂ and CA₆ (900–1500 °C) hindered densification and generated intra-particle pores. Such events differed from those observed with other CaO sources, and resulted in significantly higher pores content and lower thermal conductivity.     

Differentiation of Staphylococci from Iberian dry fermented sausages by protein fingerprinting

The Staphylococci populations in different types of Iberian dry fermented sausages from central-west Spain were identified. A simple electrophoretic method of whole-cell proteins and extracellular protein profiling was evaluated for speed of identification. This study was correlated with a 16S rRNA gene sequence analysis and biochemical identification by API Staph. A total of 81 isolates were identified by SDS-PAGE of the whole-cell proteins. These showed stable profiles in the range 99-14kDa that were clearly different for the different species, and were grouped into clusters together with the profiles of the eight reference strains. SDS-PAGE of the extracellular protein extracts provided additional characteristic banding patterns for the characterization of the Staphylococcus species present. The whole-cell SDS-PAGE showed that the predominant species was Staphylococcus saprophyticus (61.7%) followed by Staphylococcus aureus (19.7%). The identifications were confirmed by the 16S rRNA gene sequencing and by a BLAST search of the GenBank database. However, the API Staph biochemical identifications were frequently erroneous at the species level. In sum, SDS-PAGE analysis showed itself to be rapid and accurate in identifying the most commonly encountered Staphylococcus isolates in dry fermented sausages.     

Ranking of departments and researchers within a university using two different databases: Web of Science versus Scopus

In this work, we compare the difference in the number of citations compiled with Scopus as opposed to the Web of Science (WoS) with the aim of analysing the agreement among the citation rankings generated by these databases. For this, we analysed the area of Health Sciences of the University of Navarra (Spain), composed of a total of 50 departments and 864 researchers. The total number of published works reflected in the WoS during the period 1999–2005 was 2299. For each work, the number of citations in both databases was recorded. The results indicate that the works received 14.7% more citations in Scopus than in WoS. In the departments, the difference was greater in the clinical ones than in the basic ones. In the case of the rankings of citations, it was found that both databases generate similar results. The Spearman and Kendall-Tau coefficients were higher than 0.9. It was concluded that the difference in the number of citations found did not correspond to the difference of coverage of WoS and Scopus.     

Brain fMRI reactivity to smoking-related images before and during extended smoking abstinence.

[Correction Notice: An erratum for this article was reported in Vol 18(3) of Experimental and Clinical Psychopharmacology (see record 2010-11933-011). In the article the authors find it necessary to redefine the thresholding procedure used for data analyses, due to problems in the Brain Voyager software. This does not affect the main findings of the paper.] Reactivity to smoking-related cues may play a role in the maintenance of smoking behavior and may change depending on smoking status. Whether smoking cue-related functional MRI (fMRI) reactivity differs between active smoking and extended smoking abstinence states currently is unknown. We used fMRI to measure brain reactivity in response to smoking-related versus neutral images in 13 tobacco-dependent subjects before a smoking cessation attempt and again during extended smoking abstinence (52 ± 11 days) aided by nicotine replacement therapy. Prequit smoking cue induced fMRI activity patterns paralleled those reported in prior smoking cue reactivity fMRI studies. Greater fMRI activity was detected during extended smoking abstinence than during the prequit assessment subcortically in the caudate nucleus and cortically in prefrontal (BA 6, 9, 44, 46), primary somatosensory (BA 1, 2, 3), temporal (BA 22, 41, 42), parietal (BA 7, 40) anterior cingulate (BA 24, 32), and posterior cingulate (BA 31) cortex. These data suggest that during extended smoking abstinence, fMRI reactivity to smoking versus neutral stimuli persists in brain areas involved in attention, somatosensory processing, motor planning, and conditioned cue responding. In some brain regions, fMRI smoking cue reactivity is increased during extended smoking abstinence in comparison to the prequit state, which may contribute to persisting relapse vulnerability. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A line-space analysis of light-field representations

We study how to build optimal light-field or plenoptic models. We quantify geometric errors in light-field representations and show how geometric error bounds directly affect rendering artifacts. Artifacts depend on how the light-field is parameterized, stored, reconstructed and rendered. We present the rendering artifacts and relate them to the presence of geometric errors in the four most common light-field implementations.We show how to optimize a light-field model. We take an arbitrary bounded object and construct the best possible representation using each of the four parameterizations. The best representation has the least geometric error bounds. We use two geometric errors, a positional and a directional error. We also quantify pixelation artifacts. Our analysis is useful to decide how to build a light-field model. It helps select a parameterization, build an optimal representation, and choose the samplings of the parameter spaces so that geometric errors and rendering artifacts are minimized.     

Improving the training time of support vector regression algorithms through novel hyper-parameters search space reductions

The selection of hyper-parameters in support vector machines (SVM) is a key point in the training process of these models when applied to regression problems. Unfortunately, an exact method to obtain the optimal set of SVM hyper-parameters is unknown, and search algorithms are usually applied to obtain the best possible set of hyper-parameters. In general these search algorithms are implemented as grid searches, which are time consuming, so the computational cost of the SVM training process increases considerably. This paper presents a novel study of the effect of including reductions in the range of SVM hyper-parameters, in order to reduce the SVM training time, but with the minimum possible impact in its performance. The paper presents reduction in parameter C, by considering its relation with the rest of SVM hyper-parameters (γ and ε), through an approximation of the SVM model. On the other hand, we use some characteristics of the Gaussian kernel function and a previous result in the literature to obtain novel bounds for γ and ε hyper-parameters. The search space reductions proposed are evaluated in different regression problems from UCI and StatLib databases. All the experiments carried out applying the popular LIBSVM solver have shown that our approach reduces the SVM training time, maintaining the SVM performance similar to when the complete range in SVM parameters is considered.