Polycomb group (PcG) proteins are transcriptional repressors of genes involved in development and differentiation, and also maintain repression of key genes involved in the cell cycle, indirectly ...regulating cell proliferation. The human SCML2 gene, a mammalian homologue of the Drosophila PcG protein SCM, encodes two protein isoforms: SCML2A that is bound to chromatin and SCML2B that is predominantly nucleoplasmic. Here, we purified SCML2B and found that it forms a stable complex with CDK/CYCLIN/p21 and p27, enhancing the inhibitory effect of p21/p27. SCML2B participates in the G1/S checkpoint by stabilizing p21 and favoring its interaction with CDK2/CYCE, resulting in decreased kinase activity and inhibited progression through G1. In turn, CDK/CYCLIN complexes phosphorylate SCML2, and the interaction of SCML2B with CDK2 is regulated through the cell cycle. These findings highlight a direct crosstalk between the Polycomb system of cellular memory and the cell-cycle machinery in mammals.
Previous research has derived bounds on the remaining life expectancy function e(x) that connect survivorship and remaining life expectancy at two age values and therefore can be used to, among other ...things, estimate life expectancy at birth when the population's full mortality trajectory is not known. We show that the aforementioned bounds emerge from using particular two-node closed quadrature rules and prove a theorem that establishes conditions for when an n-node closed rule respects those bounds for e(x). This enables the usage of known high-accuracy rules that stay within the bounds and provide new high-accuracy estimates for e(x). We show that among this set of rules are ones that yield exact estimates for e(x). We illustrate our work empirically using life table data from French females since 1816 and discover a new empirical regularity linking life expectancy at birth in the data set to survivorship and remaining life expectancy at age 20.
Hyperextended margins are very heterogeneous along the entire length of the margin, so the definition of tectonic domains made exclusively from 2D seismic sections presents serious limitations. In ...this work we present an approach of the 3D crustal-scale structure of the West Iberia margin (WIM) by modelling eight lithospheric sections, using seismic, wells and gravity data. The continuous nature of gravity data allowed us to propose a new map of tectonic domains within the WIM. Maps of total horizontal (THD) and vertical gradients (dZ) of Bouguer anomaly have been calculated and compared with other criteria such as the crustal structure and thinning factor. This comparative analysis has been carried out on a section proposed as a model for the Western Iberian Margin (Tugend et al. in Tectonics, 2014; Cadenas et al. in Tectonics 37:758–785, 2018), and on four 2 + 1/2D gravimetric models transversal to the margin. The results point out a significant variation in the absolute values of Bouguer anomaly, thinning factor and crustal structure along the margin and, therefore, of the position of the different domain boundaries. Clear patterns that correlating the Bouguer anomaly signal and its derivatives to the tectonic domain are evidenced. Most significantly, the necking-zone and its transition to the hyperextended domain are characterized by high values of the THD of the Bouguer anomaly. The observed patterns in Bouguer anomaly and its derivatives provide a solid constraint for mapping the boundaries between different tectonic domains along the margin, even in those areas where limited deep seismic information could lead to uncertain interpretations. The results of this work can also inform on the general kinematics of the WIM.
The combination of Pegylated Liposomal Doxorubicin (PLD) plus Gemcitabine (GEM) has been previously investigated in the treatment of metastatic breast cancer (MBC). PLD is a doxorubicin formulation ...with prolonged circulation time and better tissue distribution. GEM is a nucleoside analog with nonoverlapping toxicity compared to PLD. The aim of our study was to assess efficacy, toxicity, and long‐term outcome of this combination. Patients with heavily treated MBC were retrospectively analyzed. Chemotherapy consisted of PLD 25 mg/m2 and GEM 800 mg/m2 day 1, on a three‐week schedule. Cardiac function was evaluated baseline and during treatment. Radiological response was graded according to RECIST criteria v1.1. Toxicity was scored according to CTCAE v4.0. Progression‐free survival (PFS) and overall survival (OS) were evaluated. From 2001 to 2014, 122 pts were included. Median age was 55 (range: 28‐84). Median previous treatment schedules in the metastatic scenario were 3 (range: 1‐15). Most patients received prior anthracyclines (85%). Median number of metastatic sites was 2 (range: 1‐7). Median number of cycles delivered was 5 (range: 1‐36). Overall response rate was 31% (5% complete responses; 26% partial responses). Stable and progressive diseases were observed in 32% and 26% of patients. Grade ≥3 neutropenia was observed in 29 patients (24%). Grade ≥3 hand‐foot syndrome was detected in 17 patients (14%), mostly since cycle 3 (88%). Median cumulative PLD dose was 125 mg/m2. At a median follow‐up of 101 months, median PFS and OS were 7 and 22 months, respectively. PLD‐GEM combination achieves remarkable long‐term outcomes with an acceptable toxicity profile in patients with MBC.
Multiple sclerosis (MS) is a neuroinflammatory disease whose pathogenesis remains unclear. Lysophosphatidic acid (LPA) is an endogenous phospholipid involved in multiple immune cell functions and ...dysregulated in MS. Its receptor LPA
1
is expressed in macrophages and regulates their activation, which is of interest due to the role of macrophage activation in MS in both destruction and repair. In this study, we studied the genetic deletion and pharmaceutical inhibition of LPA
1
in the mouse MS model, experimental autoimmune encephalomyelitis (EAE). LPA
1
expression was analyzed in EAE mice and MS patient immune cells. The effect of LPA and LPA
1
on macrophage activation was studied in human monocyte-derived macrophages. We show that lack of LPA
1
activity induces milder clinical EAE course and that
Lpar1
expression in peripheral blood mononuclear cells (PBMC) correlates with onset of relapses and severity in EAE. We see the same over-expression in PBMC from MS patients during relapse compared with progressive forms of the disease and in stimulated monocyte-derived macrophages. LPA induced a proinflammatory-like response in macrophages through LPA
1
, providing a plausible way in which LPA and LPA
1
dysregulation can lead to the inflammation in MS. These data show a new mechanism of LPA signaling in the MS pathogenesis, prompting further research into its use as a therapeutic target biomarker.
The Anaphase-promoting complex/cyclosome (APC/C) cofactor Cdh1 modulates cell proliferation by targeting multiple cell-cycle regulators for ubiquitin-dependent degradation. Lack of Cdh1 results in ...structural and numerical chromosome aberrations, a hallmark of genomic instability. By using a proteomic approach in Cdh1-null cells and mouse tissues, we have identified kinesin Eg5 and topoisomerase 2α as Cdh1 targets involved in the maintenance of genomic stability. These proteins are ubiquitinated and degraded through specific KEN and D boxes in a Cdh1-dependent manner. Whereas Cdh1-null cells display partial resistance to Eg5 inhibitors such as monastrol, lack of Cdh1 results in a dramatic sensitivity to Top2α poisons as a consequence of increased levels of trapped Top2α-DNA complexes. Chemical inhibition of the APC/C in cancer cells results in increased sensitivity to Top2α poisons. This work identifies in vivo targets of the mammalian APC/C-Cdh1 complex and reveals synthetic lethal interactions of relevance in anticancer treatments.
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•Several proteomic screens for APC/C-Cdh1 substrates identify Eg5 and Top2α•Overexpression of Eg5 in Cdh1-null cells results in protection against monastrol•Genetic ablation of Cdh1 results in increased susceptibility to Top2α poisons•Chemical inhibition of the APC/C sensitizes tumor cells to Top2α poisons
The anaphase-promoting complex/cyclosome (APC/C) is an E3-ubiquitin ligase that regulates the cell division cycle by targeting specific substrates for degradation. By using a combination of genetic models and proteomics, Malumbres and colleagues find additional APC/C substrates involved in the maintenance of genomic stability. One of them, topoisomerase 2α, is a relevant cancer target, and this study describes a synthetic lethal interaction that can be used for triggering death in cancer cells.
Human endogenous retroviruses (HERVs) are repetitive sequences derived from ancestral germ-line infections by exogenous retroviruses and different HERV families have been integrated in the genome. ...HERV-Fc1 in chromosome X has been previously associated with multiple sclerosis (MS) in Northern European populations. Additionally, HERV-Fc1 RNA levels of expression have been found increased in plasma of MS patients with active disease. Considering the North-South latitude gradient in MS prevalence, we aimed to evaluate the role of HERV-Fc1on MS risk in three independent Spanish cohorts.
A single nucleotide polymorphism near HERV-Fc1, rs391745, was genotyped by Taqman chemistry in a total of 2473 MS patients and 3031 ethnically matched controls, consecutively recruited from: Northern (569 patients and 980 controls), Central (883 patients and 692 controls) and Southern (1021 patients and 1359 controls) Spain. Our results were pooled in a meta-analysis with previously published data.
Significant associations of the HERV-Fc1 polymorphism with MS were observed in two Spanish cohorts and the combined meta-analysis with previous data yielded a significant association rs391745 C-allele carriers: pM-H = 0.0005; ORM-H (95% CI) = 1.27 (1.11-1.45). Concordantly to previous findings, when the analysis was restricted to relapsing remitting and secondary progressive MS samples, a slight enhancement in the strength of the association was observed pM-H = 0.0003, ORM-H (95% CI) = 1.32 (1.14-1.53).
Association of the HERV-Fc1 polymorphism rs391745 with bout-onset MS susceptibility was confirmed in Southern European cohorts.
The purpose of this paper is to report the results of ongoing research on the integration of groups at risk of exclusion, in order to facilitate decision-making processes that allow their ...consideration by social protection mechanisms. The main objectives of the research were to 000construct tools to explore and assess entry to the workforce based on skills training and risk factors. Study participants comprised groups using services in the area provided by Social Action, which included women at risk, people with disabilities, immigrants, ethnic minorities, present and former drug addicts, and other groups such as homeless people. The methodology is qualitative, through ethnographic fieldwork. We conclude that, unlike poverty and marginalisation, which manifest as an economic deficit and thus may be tackled by economic measures, social exclusion corresponds to a social deficit. Exclusion produces deficits in terms of social cohesion, in which factors related to training and the skills acquired play an essential role.
One of the major transformations in religion in contemporary societies has been the decline of church institutions and their reconstruction within a diverse network of associations, therapies, ...markets and other unconventional spiritual services. Based on extensive ethnographic fieldwork on religious behaviours and dynamics in sports contexts, and taking the similarities between sport and religion as the point of departure, this paper analyses, reflects on and theorises about the symbolic affinities of these two contemporary social institutions. The results show that symbolism converges in the religious element, tending to improve aspects related to sports ethics and establishing affective experiences among participants, with positive results for their physical and mental wellbeing. The findings indicate that a symbolic analysis of the various facets of sport is a useful approach for gaining a better understanding of this phenomenon, since besides being biological, diseases are also cultural and social, and thus, disease, religion and ritual are emotionally related.
Multiple Sclerosis (MS) is a progressive disease leading to increasing disability and costs. A literature review was carried out to identify MS costs and to estimate its economic burden in Spain. ...Areas Covered: The public electronic databases PubMed, ScienceDirect and IBECS were consulted and a manual review of communications presented at related congresses was carried out. A total of 225 references were obtained, of which 43 were finally included in the study. Expert Commentary: Three major cost groups were identified: direct healthcare costs, direct non-healthcare costs and indirect costs. There is a direct relationship between disease progression and increased costs, mainly direct non-healthcare costs (greater need for informal care) and indirect costs (greater loss of productivity). The total cost associated with MS in Spain is €1,395 million per year, and that the mean annual cost per patient is €30,050. Beyond costs, a large impact on the quality of life of patients, with an annual loss of up to 13,000 quality-adjusted life years was also estimated. MS has a large economic impact on Spanish society and a significant impact on the quality of life of patients.
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