Human GINS, a conserved DNA replication factor and candidate cancer marker

The GINS complex (a heterotetramer of Sld5, Psf1, Psf2 and Psf3) is a highly conserved DNA replication factor required for the initiation and elongation of DNA replication. GINS is believed to associate with Cdc45 and MCM proteins on replicating DNA. The interaction between GINS and MCM is also conserved in archaea. In my thesis, I explore the subcellular localisation of the GINS complex in relation to the MCM proteins and sites of DNA replication by high-resolution confocal microscopy. For these studies, I generated and carefully validated purified rabbit polyclonal and mouse monoclonal antibodies; these show a specific staining pattern by immunohistochemistry, immunoblotting and immunofluorescence. At high-resolution, all GINS antibodies produced a focal nuclear pattern, similar to that seen for the MCMs. However, confusingly, colocalisation between GINS and MCMs and between the GINS subunits themselves is poor. Investigations are continuing to understand this conundrum. Given the value of MCM proteins as specific and sensitive markers for cancer screening, I investigated whether GINS subunits also have potential diagnostic value. Sld5 and Psf3 expression is restricted to the proliferative compartment in normal tissue, but is found in the majority of cells in a wide range of dysplastic and malignant tissues, including cervix, colon and bladder. In vitro studies of tissue culture cells and cell lysates incubated in urine suggest that Sld5 protein is more stable than Mcm2 in harsh extracellular environments. In an ongoing pilot clinical study of Sld5 protein as a potential biomarker, Sld5 is readily and specifically detectable in the cellular fraction of the samples from prostate and bladder cancer patients. Work is ongoing to evaluate Sld5 protein levels in the supernatant portion of those same urine samples as an easy-to-screen diagnostic/prognostic marker for male urogenital cancers. Owing to their stability, GINS proteins hold promise as independent or complementary markers to the MCM proteins for cancer screening in harsh extracellular environments such as urine

Landing errors in the men’s floor exercise are caused by flight characteristics

Landing errors on men’s floor exercises are caused by the flight parameters. Depending of the flight phase is determined the magnitude of the landing mistake. On the sample of all gymnasts (n=97) who were competing in the qualifications of the senior Men’s European Championships 2004 in Ljubljana, we analyzed saltos which were performed by them. Variables according to the theoretical model for the evaluation of salto landings in the floor exercise were used. From the mentioned model we chose only those variables that relate to the flight phase. Axis of rotation, number of turns around longitudinal axis and initial landing height havea significant impact on the magnitude of the landing mistake

Foehn winds link climate-driven warming to ice shelf evolution in Antarctica

Author Posting. © American Geophysical Union, 2015. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Atmospheres 120 (2015): 11,037–11,057, doi:10.1002/2015JD023465.Rapid warming of the Antarctic Peninsula over the past several decades has led to extensive surface melting on its eastern side, and the disintegration of the Prince Gustav, Larsen A, and Larsen B ice shelves. The warming trend has been attributed to strengthening of circumpolar westerlies resulting from a positive trend in the Southern Annular Mode (SAM), which is thought to promote more frequent warm, dry, downsloping foehn winds along the lee, or eastern side, of the peninsula. We examined variability in foehn frequency and its relationship to temperature and patterns of synoptic-scale circulation using a multidecadal meteorological record from the Argentine station Matienzo, located between the Larsen A and B embayments. This record was further augmented with a network of six weather stations installed under the U.S. NSF LARsen Ice Shelf System, Antarctica, project. Significant warming was observed in all seasons at Matienzo, with the largest seasonal increase occurring in austral winter (+3.71°C between 1962–1972 and 1999–2010). Frequency and duration of foehn events were found to strongly influence regional temperature variability over hourly to seasonal time scales. Surface temperature and foehn winds were also sensitive to climate variability, with both variables exhibiting strong, positive correlations with the SAM index. Concomitant positive trends in foehn frequency, temperature, and SAM are present during austral summer, with sustained foehn events consistently associated with surface melting across the ice sheet and ice shelves. These observations support the notion that increased foehn frequency played a critical role in precipitating the collapse of the Larsen B ice shelf.National Science Foundation Office of Polar Programs Grant Numbers: ANT-0732983, ANT-0732467, ANT-0732921; NSF Graduate Research Fellowship Grant Number: DGE-1144086; NASA Earth and Space Science Fellowship Program Grant Number: NNX12AN48H2016-05-0

LARSEN B, RETRATO DEL CALENTAMIENTO: En la bahía Larsen B, noreste de la Península Antártica, desembocan numerosos glaciares de descarga, que son importantes reservas de agua dulce… ¿Cómo les está afectando el cambio climático?

Antártida contiene la mayor reserva de agua dulce del planeta y se encuentra en forma de hielo. El Panel Intergubernamental para el Cambio Climático reportó un aumento de 1,1 °C en la temperatura media global, lo cual preocupa a los países miembros del Tratado Antártico, entre ellos, Argentina. Para saber cómo afecta este aumento de la temperatura a las masas de hielo, el Instituto Antártico Argentino está realizando hace décadas un constante estudio de los glaciares de la Península Antártica. Se registró que, durante los últimos años, los glaciares situados en la bahía Larsen B, en el noreste de la Península Antártica, presentan un acelerado retroceso

Disease management patterns for postmenopausal women in Europe with hormone-receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer.

peer reviewedAbstract Background: International guidelines for hormone-receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (BC) recommend sequential lines of hormonal therapy (HT), and only recommend chemotherapy for patients with extensive visceral involvement or rapidly progressive disease. This study evaluated actual physician-reported treatments for advanced BC in Europe. Methods: We conducted a retrospective chart review of 355 postmenopausal women with HR+, HER2- advanced BC who progressed on >/=1 line of HT (adjuvant or advanced) and completed >/=1 line of chemotherapy (advanced). Treatment choice was evaluated for each line of therapy. Results: Of 355 patients, 111 (31%) received first-line chemotherapy, whereas 218 (61%) and 26 (7%) switched from HT to chemotherapy in second and third line, respectively. More patients receiving first-line HT had bone metastases (73% vs 27% chemotherapy). Patients treated with first-line chemotherapy had more brain (12% vs 3% HT) or extensive liver (13% vs 6% HT) metastases. Subgroup analysis of 188 patients who received first-line HT and had de novo advanced BC or relapsed/recurrent disease more than 1 year after adjuvant therapy found that the majority (89%; n = 167) of these patients switched to chemotherapy in second line. However, among these 167 patients, 27% had no significant changes in metastases between first and second line. Among the 73% of patients who had significant changes in metastases, 20% had no brain metastases or extensive visceral disease. Conclusions: Our study suggests that the guideline-recommended use of multiple HT lines is open to interpretation and that optimal treatment for European postmenopausal women with HR+, HER2- advanced BC who responded to HT may not be achieved

DNA replication: archaeal oriGINS

GINS is an essential eukaryotic DNA replication factor that is found in a simplified form in Archaea. A new study in this issue of BMC Biology reveals the first structure of the archaeal GINS complex. The structure reveals the anticipated similarity to the previously determined eukaryotic complex but also has some intriguing differences in the relative disposition of subunit domains

International Retrospective Chart Review of Treatment Patterns in Severe Familial Mediterranean Fever, Tumor Necrosis Factor Receptor–Associated Periodic Syndrome, and Mevalonate Kinase Deficiency/Hyperimmunoglobulinemia D Syndrome

Objective: Periodic fever syndrome (PFS) conditions are characterized by recurrent attacks of fever and localized inflammation. This study examined the diagnostic pathway and treatments at tertiary centers for familial Mediterranean fever (FMF), tumor necrosis factor receptor–associated periodic syndrome (TRAPS), and mevalonate kinase deficiency (MKD)/hyperimmunoglobulinemia D syndrome (HIDS). Methods: PFS specialists at medical centers in the US, the European Union, and the eastern Mediterranean participated in a retrospective chart review, providing de‐identified data in an electronic case report form. Patients were treated between 2008 and 2012, with at least 1 year of followup; all had clinical and/or genetically proven disease and were on/eligible for biologic treatment. Results: A total of 134 patients were analyzed: FMF (n = 49), TRAPS (n = 47), and MKD/HIDS (n = 38). Fever was commonly reported as severe across all indications. Other frequently reported severe symptoms were serositis for FMF patients and elevated acute‐phase reactants and gastrointestinal upset for TRAPS and MKD/HIDS. A long delay from disease onset to diagnosis was seen within TRAPS and MKD/HIDS (5.8 and 7.1 years, respectively) compared to a 1.8‐year delay in FMF patients. An equal proportion of TRAPS patients first received anti–interleukin‐1 (anti‐IL‐1) and anti–tumor necrosis factor (anti‐TNF) biologic agents, whereas IL‐1 blockade was the main choice for FMF patients resistant to colchicine and MKD/HIDS patients. For TRAPS patients, treatment with anakinra versus anti‐TNF treatments as first biologic agent resulted in significantly higher clinical and biochemical responses (P = 0.03 and P < 0.01, respectively). No significant differences in responses were observed between biologic agents among other cohorts. Conclusion: Referral patterns and diagnostic delays highlight the need for greater awareness and improved diagnostics for PFS. This real‐world treatment assessment supports the need for further refinement of treatment practices

Coupling of DNA binding and helicase activity is mediated by a conserved loop in the MCM protein

Minichromosome maintenance (MCM) helicases are the presumptive replicative helicases, thought to separate the two strands of chromosomal DNA during replication. In archaea, the catalytic activity resides within the C-terminal region of the MCM protein. In Methanothermobacter thermautotrophicus the N-terminal portion of the protein was shown to be involved in protein multimerization and binding to single and double stranded DNA. MCM homologues from many archaeal species have highly conserved predicted amino acid similarity in a loop located between β7 and β8 in the N-terminal part of the molecule. This high degree of conservation suggests a functional role for the loop. Mutational analysis and biochemical characterization of the conserved residues suggest that the loop participates in communication between the N-terminal portion of the helicase and the C-terminal catalytic domain. Since similar residues are also conserved in the eukaryotic MCM proteins, the data presented here suggest a similar coupling between the N-terminal and catalytic domain of the eukaryotic enzyme