State space modelling and data analysis exercises in LISA Pathfinder

LISA Pathfinder is a mission planned by the European Space Agency to test the key technologies that will allow the detection of gravitational waves in space. The instrument on-board, the LISA Technology package, will undergo an exhaustive campaign of calibrations and noise characterisation campaigns in order to fully describe the noise model. Data analysis plays an important role in the mission and for that reason the data analysis team has been developing a toolbox which contains all the functionalities required during operations. In this contribution we give an overview of recent activities, focusing on the improvements in the modelling of the instrument and in the data analysis campaigns performed both with real and simulated data.Comment: Plenary talk presented at the 9th International LISA Symposium, 21-25 May 2012, Pari

Estrategia invasiva de rutina en el síndrome coronario agudo sin elevación del segmento ST con disfunción renal. Resultados del registro ARIAM-SEMICYUC

Objetivo: Evaluar la utilización y efectividad de la estrategia invasiva de rutina (EIR) en pacientes con síndrome coronario agudo sin elevación de ST con disfunción renal en el mundo real. Métodos: Estudio de cohortes retrospectivo basado en el registro ARIAM-SEMICYUC (años 2011- 2014). Se consideró que había disfunción renal cuando el GFR (Cockroft-Gault) era menor de 60 ml/min (disfunción moderada) o de 30 ml/min (disfunción grave). Se excluyeron los pacientes en los que la coronariografía precoz (< 72 h) se debió a shock cardiogénico o isquemia recurrente. El desenlace primario fue la mortalidad hospitalaria. El control del confounding se realizó mediante un análisis de propensión. Resultados: Se analizan 4.279 pacientes, de los cuales un 26% tenía disfunción renal moderada y un 5% disfunción grave. Los pacientes con disfunción renal presentaron una mayor gravedad y comorbilidad, una mayor mortalidad hospitalaria (8,6 frente a 1,8%) y una menor utilización de la EIR (40 frente a 52%). Las OR ajustadas mediante emparejamiento para pacientes sin/con disfunción renal fueron de 0,38 (intervalo de confianza al 95% [IC95%] de 0,17 a 0,81) y 0,52 (IC95% de 0,32 a 0,87), respectivamente (p de interacción 0,4779). El impacto de la EIR (diferencia de riesgos ajustada) fue mayor en el grupo con disfunción renal (−5,1%, IC95% entre −8,1 y −2,1, frente a −1,6%, IC95% entre −2,6 y −0,6, p de interacción = 0,0335). Tampoco se detectó interacción significativa respecto a los demás enlaces considerados (mortalidad en UCI o a los 30 días, riesgo combinado de muerte o infarto, fracaso renal agudo o hemorragias moderadas/graves). Conclusiones: Los resultados evidencian que la efectividad de la EIR es similar en pacientes con función renal normal o reducida y alertan sobre una infrautilización de esta estrategia en estos últimos.Objective: To evaluate the use and effectiveness of a routine invasive strategy (RIS) in patients with acute coronary syndrome without persistent ST-segment elevation with renal dysfunction in the real world scenario. Methods: A retrospective cohort study based on the ARIAM-SEMICYUC Registry (2011-2014) was carried out. Renal dysfunction was defined as GFR (Cockroft-Gault)<60ml/min (moderate dysfunction) or<30ml/min (severe dysfunction). Patients in which early angiography (<72h) was performed due to cardiogenic shock or recurrent myocardial ischemia were excluded. The primary endpoint was hospital mortality. Confounding factors were controlled using propensity score analysis. Results: A total of 4,279 patients were analyzed, of which 26% had moderate renal dysfunction and 5% severe dysfunction. Patients with renal dysfunction had greater severity and comorbidity, higher hospital mortality (8.6 vs. 1.8%), and lesser use of the RIS (40 vs. 52%). The adjusted OR for mortality in patients without/with renal dysfunction were 0.38 (95% confidence interval [95%CI] 0.17 to 0.81) and 0.52 (95%CI 0.32 to 0.87), respectively (interaction P-value=.4779). The impact (adjusted risk difference) of RIS was higher in the group with renal dysfunction (-5.1%, 95%CI -8.1 to -2.1 vs. -1.6%, 95%CI -2.6 to -0.6; interaction P-value=.0335). No significant interaction was detected for the other endpoints considered (ICU mortality, 30-day mortality, myocardial infarction, acute renal failure or moderate/severe bleeding).Conclusions: The results suggest that the effectiveness of IRS is similar in patients with normal or abnormal renal function, and alert to the under-utilization of this strategy in such patients

HDAC7 Is a Repressor of Myeloid Genes Whose Downregulation Is Required for Transdifferentiation of Pre-B Cells into Macrophages

B lymphopoiesis is the result of several cell-commitment, lineage-choice, and differentiation processes. Every differentiation step is characterized by the activation of a new, lineage-specific, genetic program and the extinction of the previous one. To date, the central role of specific transcription factors in positively regulating these distinct differentiation processes to acquire a B cell-specific genetic program is well established. However, the existence of specific transcriptional repressors responsible for the silencing of lineage inappropriate genes remains elusive. Here we addressed the molecular mechanism behind repression of non-lymphoid genes in B cells. We report that the histone deacetylase HDAC7 was highly expressed in pre-B cells but dramatically down-regulated during cellular lineage conversion to macrophages. Microarray analysis demonstrated that HDAC7 re-expression interfered with the acquisition of the gene transcriptional program characteristic of macrophages during cell transdifferentiation; the presence of HDAC7 blocked the induction of key genes for macrophage function, such as immune, inflammatory, and defense response, cellular response to infections, positive regulation of cytokines production, and phagocytosis. Moreover, re-introduction of HDAC7 suppressed crucial functions of macrophages, such as the ability to phagocytose bacteria and to respond to endotoxin by expressing major pro-inflammatory cytokines. To gain insight into the molecular mechanisms mediating HDAC7 repression in pre-B cells, we undertook co-immunoprecipitation and chromatin immunoprecipitation experimental approaches. We found that HDAC7 specifically interacted with the transcription factor MEF2C in pre-B cells and was recruited to MEF2 binding sites located at the promoters of genes critical for macrophage function. Thus, in B cells HDAC7 is a transcriptional repressor of undesirable genes. Our findings uncover a novel role for HDAC7 in maintaining the identity of a particular cell type by silencing lineage-inappropriate genes

High Smac/DIABLO expression is associated with early local recurrence of cervical cancer

<p>Abstract</p> <p>Background</p> <p>In a recent pilot report, we showed that Smac/DIABLO mRNA is expressed <it>de novo </it>in a subset of cervical cancer patients. We have now expanded this study and analyzed Smac/DIABLO expression in the primary lesions in 109 cervical cancer patients.</p> <p>Methods</p> <p>We used immunohistochemistry of formalin-fixed, paraffin-embedded tissue sections to analyze Smac/DIABLO expression in the 109 primary lesions. Seventy-eight samples corresponded to epidermoid cervical cancer and 31 to cervical adenocarcinoma. The median follow up was 46.86 months (range 10–186).</p> <p>Results</p> <p>Smac/DIABLO was expressed in more adenocarcinoma samples than squamous tumours (71% vs 50%; p = 0.037). Among the pathological variables, a positive correlation was found between Smac/DIABLO immunoreactivity and microvascular density, a marker for angiogenesis (p = 0.04). Most importantly, Smac/DIABLO immunoreactivity was associated with a higher rate of local recurrence in squamous cell carcinoma (p = 0.002, log rank test). No association was found between Smac/DIABLO and survival rates.</p> <p>Conclusion</p> <p>Smac/DIABLO expression is a potential marker for local recurrence in cervical squamous cell carcinoma patients.</p

Ankyrin is the major oxidised protein in erythrocyte membranes from end-stage renal disease patients on chronic haemodialysis and oxidation is decreased by dialysis and vitamin C supplementation

Chronically haemodialysed end-stage renal disease patients are at high risk of morbidity arising from complications of dialysis, the underlying pathology that has led to renal disease and the complex pathology of chronic kidney disease. Anaemia is commonplace and its origins are multifactorial, involving reduced renal erythropoietin production, accumulation of uremic toxins and an increase in erythrocyte fragility. Oxidative damage is a common risk factor in renal disease and its co-morbidities and is known to cause erythrocyte fragility. Therefore, we have investigated the hypothesis that specific erythrocyte membrane proteins are more oxidised in end-stage renal disease patients and that vitamin C supplementation can ameliorate membrane protein oxidation. Eleven patients and 15 control subjects were recruited to the study. Patients were supplemented with 2 × 500 mg vitamin C per day for 4 weeks. Erythrocyte membrane proteins were prepared pre- and post-vitamin C supplementation for determination of protein oxidation. Total protein carbonyls were reduced by vitamin C supplementation but not by dialysis when investigated by enzyme linked immunosorbent assay. Using a western blot to detect oxidised proteins, one protein band, later identified as containing ankyrin, was found to be oxidised in patients but not controls and was reduced significantly by 60% in all patients after dialysis and by 20% after vitamin C treatment pre-dialysis. Ankyrin oxidation analysis may be useful in a stratified medicines approach as a possible marker to identify requirements for intervention in dialysis patients

The LISA Pathfinder Mission

LISA Pathfinder (formerly known as SMART-2) is an European Space Agency mission designed to pave the way for the joint ESA/NASA Laser Interferometer Space Antenna (LISA) mission by testing in flight the critical technologies required for space-borne gravitational wave detection; it will put two test masses in a near-perfect gravitational free-fall and control and measure their motion with unprecedented accuracy. This is achieved through technology comprising inertial sensors, high precision laser metrology, drag-free control, and an ultra precise micro-Newton propulsion system. LISA Pathfinder (LPF) essentially mimics one arm of spaceborne gravitational wave detectors by shrinking the million kilometre scale armlengths down to a few tens of centimetres, giving up the sensitivity to gravitational waves, but keeping the measurement technology. The scientific objective of the LISA Pathfinder mission consists then of the first in-flight test of low frequency gravitational wave detection metrology. In this paper I will give a brief overview of the mission, focusing on scientific and technical goals

Ghrelin, Sleep Reduction and Evening Preference: Relationships to CLOCK 3111 T/C SNP and Weight Loss

Circadian Locomotor Output Cycles Kaput (CLOCK), an essential element of the positive regulatory arm in the human biological clock, is involved in metabolic regulation. The aim was to investigate the behavioral (sleep duration, eating patterns and chronobiological characteristics) and hormonal (plasma ghrelin and leptin concentrations) factors which could explain the previously reported association between the CLOCK 3111T/C SNP and weight loss.We recruited 1495 overweight/obese subjects (BMI: 25-40 kg/m(2)) of 20-65 y. who attended outpatient obesity clinics in Murcia, in southeastern Spain. We detected an association between the CLOCK 3111T/C SNP and weight loss, which was particularly evident after 12-14 weeks of treatment (P = 0.038). Specifically, carriers of the minor C allele were more resistant to weight loss than TT individuals (Mean±SEM) (8.71±0.59 kg vs 10.4±0.57 kg) C and TT respectively. In addition, our data show that minor C allele carriers had: 1. shorter sleep duration Mean ± SEM (7.0±0.05 vs 7.3±0.05) C and TT respectively (P = 0.039), 2. higher plasma ghrelin concentrations Mean ± SEM (pg/ml) (1108±49 vs 976±47)(P = 0.034); 3. delayed breakfast time; 4. evening preference and 5. less compliance with a Mediterranean Diet pattern, as compared with TT homozygotes.Sleep reduction, changes in ghrelin values, alterations of eating behaviors and evening preference that characterized CLOCK 3111C carriers could be affecting weight loss. Our results support the hypothesis that the influence of the CLOCK gene may extend to a broad range of variables linked with human behaviors

BioMart Central Portal: an open database network for the biological community

BioMart Central Portal is a first of its kind, community-driven effort to provide unified access to dozens of biological databases spanning genomics, proteomics, model organisms, cancer data, ontology information and more. Anybody can contribute an independently maintained resource to the Central Portal, allowing it to be exposed to and shared with the research community, and linking it with the other resources in the portal. Users can take advantage of the common interface to quickly utilize different sources without learning a new system for each. The system also simplifies cross-database searches that might otherwise require several complicated steps. Several integrated tools streamline common tasks, such as converting between ID formats and retrieving sequences. The combination of a wide variety of databases, an easy-to-use interface, robust programmatic access and the array of tools make Central Portal a one-stop shop for biological data querying. Here, we describe the structure of Central Portal and show example queries to demonstrate its capabilities

Inhibition of Specific NF-κB Activity Contributes to the Tumor Suppressor Function of 14-3-3σ in Breast Cancer

14-3-3σ is frequently lost in human breast cancers by genetic deletion or promoter methylation. We have now investigated the involvement of 14-3-3σ in the termination of NF-κB signal in mammary cells and its putative role in cancer relapse and metastasis. Our results show that 14-3-3σ regulates nuclear export of p65-NF-κB following chronic TNFα stimulation. Restoration of 14-3-3σ in breast cancer cells reduces migration capacity and metastatic abilities in vivo. By microarray analysis, we have identified a genetic signature that responds to TNFα in a 14-3-3σ-dependent manner and significantly associates with different breast and other types of cancer. By interrogating public databases, we have found that over-expression of this signature correlates with poor relapse-free survival in breast cancer patients. Finally, screening of 96 human breast tumors showed that NF-κB activation strictly correlates with the absence of 14-3-3σ and it is significantly associated with worse prognosis in the multivariate analysis. Our findings identify a genetic signature that is important for breast cancer prognosis and for future personalized treatments based on NF-κB targeting