Rationale, experimental data, and emerging clinical evidence on early and preventive use of levosimendan in patients with ventricular dysfunction

Acute ventricular dysfunction (AVD) is a complex condition with substantial morbidity and mortality, still featuring unique therapeutic challenges. Levosimendan is a calcium sensitizer and ATP-dependent potassium channel opener that was developed as an inodilating drug for the treatment of acute heart failure and cardiogenic shock. Differently from other more widely used inotropic agents, levosimendan has some exclusive characteristics, in terms of mechanisms of action, pharmacodynamic profile, and haemodynamic effects. This may have important clinical implications. In particular, in patients with AVD or in patients with pre-existing severe ventricular impairment undergoing planned myocardial stress, the administration of levosimendan before the onset of overt symptoms or before cardiovascular therapeutic procedures may have the potential to bridge the patient through the critical phase. In this review, we will focus on the rationale, the existing experimental data, and the emerging clinical experience supporting an early, even preventive use of levosimendan in severe ventricular dysfunction, beyond its recognized indications

Combining role-play with interactive simulation to motivate informed climate action: Evidence from the World Climate simulation

Climate change communication efforts grounded in the information deficit model have largely failed to close the gap between scientific and public understanding of the risks posed by climate change. In response, simulations have been proposed to enable people to learn for themselves about this complex and politically charged topic. Here we assess the impact of a widely-used simulation, World Climate, which combines a socially and emotionally engaging role-play with interactive exploration of climate change science through the C-ROADS climate simulation model. Participants take on the roles of delegates to the UN climate negotiations and are challenged to create an agreement that meets international climate goals. Their decisions are entered into C-ROADS, which provides immediate feedback about expected global climate impacts, enabling them to learn about climate change while experiencing the social dynamics of negotiations. We assess the impact of World Climate by analyzing pre- and post-survey results from >2,000 participants in 39 sessions in eight nations. We find statistically significant gains in three areas: (i) knowledge of climate change causes, dynamics and impacts; (ii) affective engagement including greater feelings of urgency and hope; and (iii) a desire to learn and do more about climate change. Contrary to the deficit model, gains in urgency were associated with gains in participants’ desire to learn more and intent to act, while gains in climate knowledge were not. Gains were just as strong among American participants who oppose government regulation of free markets–a political ideology that has been linked to climate change denial in the US–suggesting the simulation’s potential to reach across political divides. The results indicate that World Climate offers a climate change communication tool that enables people to learn and feel for themselves, which together have the potential to motivate action informed by science.National Science Foundation (U.S.) (grant DUE-124558)National Science Foundation (U.S.) (grant ICEER-1701062

KAT Ligation for Rapid and Facile Covalent Attachment of Biomolecules to Surfaces

The efficient and bioorthogonal chemical ligation reaction between potassium acyltrifluoroborates (KATs) and hydroxylamines (HAs) was used for the surface functionalization of a self-assembled monolayer (SAM) with biomolecules. An alkane thioether molecule with one terminal KAT group (S-KAT) was synthesized and adsorbed onto a gold surface, placing a KAT group on the top of the monolayer (KAT-SAM). As an initial test case, an aqueous solution of a hydroxylamine (HA) derivative of poly(ethylene glycol) (PEG) (HA-PEG) was added to this KAT-SAM at room temperature to perform the surface KAT ligation. Quartz crystal microbalance with dissipation (QCM-D) monitoring confirmed the rapid attachment of the PEG moiety onto the SAM. By surface characterization methods such as contact angle and ellipsometry, the attachment of PEG layer was confirmed, and covalent amide-bond formation was established by X-ray photoelectron spectroscopy (XPS). In a proof-of-concept study, the applicability of this surface KAT ligation for the attachment of biomolecules to surfaces was tested using a model protein, green fluorescent protein (GFP). A GFP was chemically modified with an HA linker to synthesize HA-GFP and added to the KAT-SAM under aqueous dilute conditions. A rapid attachment of the GFP on the surface was observed in real time by QCM-D. Despite the fact that such biomolecules have a variety of unprotected functional groups within their structures, the surface KAT ligation proceeded rapidly in a chemoselective manner. Our results demonstrate the versatility of the KAT ligation for the covalent attachment of a variety of water-soluble molecules onto SAM surfaces under dilute and biocompatible conditions to form stable, natural amide bonds

Construction and Modelling of an Inducible Positive Feedback Loop Stably Integrated in a Mammalian Cell-Line

Understanding the relationship between topology and dynamics of transcriptional regulatory networks in mammalian cells is essential to elucidate the biology of complex regulatory and signaling pathways. Here, we characterised, via a synthetic biology approach, a transcriptional positive feedback loop (PFL) by generating a clonal population of mammalian cells (CHO) carrying a stable integration of the construct. The PFL network consists of the Tetracycline-controlled transactivator (tTA), whose expression is regulated by a tTA responsive promoter (CMV-TET), thus giving rise to a positive feedback. The same CMV-TET promoter drives also the expression of a destabilised yellow fluorescent protein (d2EYFP), thus the dynamic behaviour can be followed by time-lapse microscopy. The PFL network was compared to an engineered version of the network lacking the positive feedback loop (NOPFL), by expressing the tTA mRNA from a constitutive promoter. Doxycycline was used to repress tTA activation (switch off), and the resulting changes in fluorescence intensity for both the PFL and NOPFL networks were followed for up to 43 h. We observed a striking difference in the dynamics of the PFL and NOPFL networks. Using non-linear dynamical models, able to recapitulate experimental observations, we demonstrated a link between network topology and network dynamics. Namely, transcriptional positive autoregulation can significantly slow down the “switch off” times, as comparared to the nonautoregulatated system. Doxycycline concentration can modulate the response times of the PFL, whereas the NOPFL always switches off with the same dynamics. Moreover, the PFL can exhibit bistability for a range of Doxycycline concentrations. Since the PFL motif is often found in naturally occurring transcriptional and signaling pathways, we believe our work can be instrumental to characterise their behaviour

Changes in vegetation composition and structure following livestock exclusion in a temperate fluvial wetland

Questions: Responses of wetland systems to grazing can be highly variable with both positive or negative responses. However, the sustainable use of wetlands for grazing will depend on the management implemented and the resilience of each type of them. In this context, we addressed the question: will the vegetation in the studied wetland be able to recover its structural and functional parameters in the short term after livestock exclusion?. Location: Temperate fluvial wetlands in the middle Delta of the Paraná River, Argentina, South America. Methods: We evaluated the effect of cattle ranching on vegetation composition and diversity by determining changes in species richness and evenness, biomass (green and dry vegetative, and reproductive biomass), and litter content. We also analyzed the changes in biomass of weeds and of species according to their forage quality, toxicity, and growth form. We applied a randomized block design (by topographic position) with repeated measures over time, using livestock exclusion as treatment. Results: After 16 months, livestock exclusion affected vegetation species richness, but did not have a significant effect on diversity due to a slightly compensatory effect of evenness. Species composition differed markedly among treatments over time. There was an increase in dry and green vegetative biomass and litter content after eight months of exclusion, while changes in reproductive biomass occurred later. The increase in these variables was closely related to changes in biomass of species with erect habit and good forage quality. Conclusions: Livestock exclusion increased the forage value for the studied wetland by the development of natural palatable species typical of these environments. This shift in species composition promoted a higher production in biomass in the ungrazed areas. This suggests a remarkable recovery of the structural and functional parameters of the vegetation communities in the short term (two years).Fil: Magnano, Andrea Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Investigaciones de las Zonas Áridas. Provincia de Mendoza. Instituto Argentino de Investigaciones de las Zonas Áridas. Universidad Nacional de Cuyo. Instituto Argentino de Investigaciones de las Zonas Áridas; ArgentinaFil: Krug, Cecilia Pamela. Universidad Nacional de San Martín. Instituto de Investigación e Ingeniería Ambiental. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación e Ingeniería Ambiental; ArgentinaFil: Casa, Valeria. Universidad Nacional de San Martín. Instituto de Investigación e Ingeniería Ambiental. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación e Ingeniería Ambiental; ArgentinaFil: Quintana, Ruben Dario. Universidad Nacional de San Martín. Instituto de Investigación e Ingeniería Ambiental. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación e Ingeniería Ambiental; Argentin

An Integrated Microfluidic Device for Monitoring Changes in Nitric Oxide Production in Single T-Lymphocyte (Jurkat) Cells

A considerable amount of attention has been focused on the analysis of single cells in an effort to better understand cell heterogeneity in cancer and neurodegenerative diseases. Although microfluidic devices have several advantages for single cell analysis, few papers have actually demonstrated the ability of these devices to monitor chemical changes in perturbed biological systems. In this paper, a new microfluidic channel manifold is described that integrates cell transport, lysis, injection, electrophoretic separation, and fluorescence detection into a single device, making it possible to analyze individual cells at a rate of 10 cells/min in an automated fashion. The system was employed to measure nitric oxide (NO) production in single T-lymphocytes (Jurkat cells) using a fluorescent marker, 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM DA). The cells were also labeled with 6-carboxyfluorescein diacetate (6-CFDA) as an internal standard. The NO production by control cells was compared to that of cells stimulated using lipopolysaccharide (LPS), which is known to cause the expression of inducible nitric oxide synthase (iNOS) in immune-type cells. Statistical analysis of the resulting electropherograms from a population of cells indicated a twofold increase in NO production in the induced cells. These results compare nicely to a recently published bulk cell analysis of NO

A database of the coseismic effects following the 30 October 2016 Norcia earthquake in Central Italy

We provide a database of the coseismic geological surface effects following the Mw 6.5 Norcia earthquake that hit central Italy on 30 October 2016. This was one of the strongest seismic events to occur in Europe in the past thirty years, causing complex surface ruptures over an area of >400 km 2. The database originated from the collaboration of several European teams (Open EMERGEO Working Group; about 130 researchers) coordinated by the Istituto Nazionale di Geofisica e Vulcanologia. The observations were collected by performing detailed field surveys in the epicentral region in order to describe the geometry and kinematics of surface faulting, and subsequently of landslides and other secondary coseismic effects. The resulting database consists of homogeneous georeferenced records identifying 7323 observation points, each of which contains 18 numeric and string fields of relevant information. This database will impact future earthquake studies focused on modelling of the seismic processes in active extensional settings, updating probabilistic estimates of slip distribution, and assessing the hazard of surface faulting