Observing The Mediterranean Sea from space: 21 years of Pathfinder-AVHRR Sea Surface Temperatures (1985 to 2005). Re-analysis and validation

International audienceThe time series of satellite infrared AVHRR data from 1985 to 2005 has been used to produce a daily series of optimally interpolated SST maps over the regular grid of the operational MFSTEP OGCM model of the Mediterranean basin. A complete validation of this OISST (Optimally Interpolated Sea Surface Temperature) product with in situ measurements has been performed in order to exclude any possibility of spurious trends due to instrumental calibration errors/shifts or algorithms malfunctioning related to local geophysical factors. The validation showed that satellite OISST is able to reproduce in situ measurements with a mean bias of less than 0.1°C and RMSE of about 0.5°C and that errors do not drift with time or with the percent interpolation error

P1367Effects of levosimendan therapy in patients with severe functional mitral regurgitation and chronic heart failure undergoing mitraclip implantation: a single-centre experience

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Volatile compared with total intravenous anaesthesia in patients undergoing high-risk cardiac surgery: a randomized multicentre study

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Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion

In cardiac surgery, postoperative low cardiac output has been shown to correlate with increased rates of organ failure and mortality. Catecholamines have been the standard therapy for many years, although they carry substantial risk for adverse cardiac and systemic effects, and have been reported to be associated with increased mortality. On the other hand, the calcium sensitiser and potassium channel opener levosimendan has been shown to improve cardiac function with no imbalance in oxygen consumption, and to have protective effects in other organs. Numerous clinical trials have indicated favourable cardiac and non-cardiac effects of preoperative and perioperative administration of levosimendan. A panel of 27 experts from 18 countries has now reviewed the literature on the use of levosimendan in on-pump and off-pump coronary artery bypass grafting and in heart valve surgery. This panel discussed the published evidence in these various settings, and agreed to vote on a set of questions related to the cardioprotective effects of levosimendan when administered preoperatively, with the purpose of reaching a consensus on which patients could benefit from the preoperative use of levosimendan and in which kind of procedures, and at which doses and timing should levosimendan be administered. Here, we present a systematic review of the literature to report on the completed and ongoing studies on levosimendan, including the newly commenced LEVO-CTS phase III study (NCT02025621), and on the consensus reached on the recommendations proposed for the use of preoperative levosimendan

SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis.

BACKGROUND: Loss of motor neurons in amyotrophic lateral sclerosis (ALS) leads to progressive paralysis and death. Dysregulation of thousands of RNA molecules with roles in multiple cellular pathways hinders the identification of ALS-causing alterations over downstream changes secondary to the neurodegenerative process. How many and which of these pathological gene expression changes require therapeutic normalisation remains a fundamental question. METHODS: Here, we investigated genome-wide RNA changes in C9ORF72-ALS patient-derived neurons and Drosophila, as well as upon neuroprotection taking advantage of our gene therapy approach which specifically inhibits the SRSF1-dependent nuclear export of pathological C9ORF72-repeat transcripts. This is a critical study to evaluate (i) the overall safety and efficacy of the partial depletion of SRSF1, a member of a protein family involved itself in gene expression, and (ii) a unique opportunity to identify neuroprotective RNA changes. RESULTS: Our study shows that manipulation of 362 transcripts out of 2257 pathological changes, in addition to inhibiting the nuclear export of repeat transcripts, is sufficient to confer neuroprotection in C9ORF72-ALS patient-derived neurons. In particular, expression of 90 disease-altered transcripts is fully reverted upon neuroprotection leading to the characterisation of a human C9ORF72-ALS disease-modifying gene expression signature. These findings were further investigated in vivo in diseased and neuroprotected Drosophila transcriptomes, highlighting a list of 21 neuroprotective changes conserved with 16 human orthologues in patient-derived neurons. We also functionally validated the high neuroprotective potential of one of these disease-modifying transcripts, demonstrating that inhibition of ALS-upregulated human KCNN1-3 (Drosophila SK) voltage-gated potassium channel orthologs mitigates degeneration of human motor neurons and Drosophila motor deficits. CONCLUSIONS: Strikingly, the partial depletion of SRSF1 leads to expression changes in only a small proportion of disease-altered transcripts, indicating that not all RNA alterations need normalization and that the gene therapeutic approach is safe in the above preclinical models as it does not disrupt globally gene expression. The efficacy of this intervention is also validated at genome-wide level with transcripts modulated in the vast majority of biological processes affected in C9ORF72-ALS. Finally, the identification of a characteristic signature with key RNA changes modified in both the disease state and upon neuroprotection also provides potential new therapeutic targets and biomarkers.This work was initiated with the Medical Research Council (MRC) grant MR/M010864/1 (KN, GMH, PJS) and the MND Association grant Hautbergue/Apr16/846–791 (GMH, LF, AJW, PJS, LMC). This research was further supported by the MRC New Investigator research grant MR/R024162/1 (GMH) and the Biotechnology and Biological Sciences Research Council (BBSRC) grant BB/S005277/1 (GMH). LC was supported by H2020-EU EU Marie Curie fellowship CONTESSA (ID: 660388). CDSS is funded by an AstraZeneca Post-Doctoral award. LF was funded by the Thierry Latran Foundation (FTLAAP2016/ Astrocyte secretome) and is currently supported by the MND Association grant Apr16/848–791 and the Academy of Medical Sciences Springboard Award. AJW was supported by MRC core funding (MC_UU_00015/6) and ERC Starting grant (DYNAMITO; 309742). GMH also reports grants Apr17/854–791 from the MND Association, Thierry Latran FTLAAP2016/ Astrocyte secretome and Royal Society International Exchanges grant IEC\R3\17010 during the course of this study. MA acknowledge grants from Alzheimer’s Research UK (ARUK-PG2018B-005), European Research Council (ERC Advanced Award 294745) and MRC DPFS (129016). PJS is supported as an NIHR Senior Investigator Investigator (NF-SI-0617–10077) and by the MND Association (AMBRoSIA 972–797) and MRC grant MR/S004920/1

A coupled optical-thermal-electrical model to predict the performance of hybrid PV/T-CCPC roof-top systems

A crossed compound parabolic concentrator (CCPC) is applied into a photovoltaic/thermal (PV/T) hybrid solar collector, i.e. concentrating PV/T (CPV/T) collector, to develop new hybrid roof-top CPV/T systems. However, to optimise the system configuration and operational parameters as well as to predict their performances, a coupled optical, thermal and electrical model is essential. We establish this model by integrating a number of submodels sourced from literature as well as from our recent work on incidence-dependent optical efficiency, six-parameter electrical model and scaling law for outdoor conditions. With the model, electrical performance and cell temperature are predicted on specific days for the roof-top systems installed in Glasgow, Penryn and Jaen. Results obtained by the proposed model reasonably agree with monitored data and it is also clarified that the systems operate under off-optimal operating condition. Long-term electric performance of the CPV/T systems is estimated as well. In addition, effects of transient terms in heat transfer and diffuse solar irradiance on electric energy are identified and discussed

Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51

Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51. First, we demonstrated that PARP1 is upregulated in CRC-SCs resistant to several replication poisons and RSR inhibitors (RSRi). In these cells, PARP1 modulates replication fork speed resulting in low constitutive RS. Second, we showed that MRE11 and RAD51 cooperate in the genoprotection and mitosis execution of PARP1-upregulated CRC-SCs. These roles represent therapeutic vulnerabilities for CSCs. Indeed, PARP1i sensitized CRC-SCs to ATRi/CHK1i, inducing replication catastrophe, and prevented the development of resistance to CHK1i. Also, MRE11i + RAD51i selectively killed PARP1-upregulated CRC-SCs via mitotic catastrophe. These results provide the rationale for biomarker-driven clinical trials in CRC using distinct RSRi combinations

Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases