Janus PEG-based dendrimers for use in combination therapy: controlled multi-drug loading and sequential release

The increasing use of drug combinations to treat disease states, such as cancer, calls for improved delivery systems that are able to deliver multiple agents. Herein, we report a series of novel Janus dendrimers with potential for use in combination therapy. Different generations (first and second) of PEG-based dendrons containing two different “model drugs”, benzyl alcohol (BA) and 3-phenylpropionic acid (PPA), were synthesized. BA and PPA were attached via two different linkers (carbonate and ester, respectively) to promote differential drug release. The four dendrons were coupled together via (3 + 2) cycloaddition chemistries to afford four Janus dendrimers, which contained varying amounts and different ratios of BA and PPA, namely, (BA)2-G1-G1-(PPA)2, (BA)4-G2-G1-(PPA)2, (BA)2-G1-G2-(PPA)4, and (BA)4-G2-G2-(PPA)4. Release studies in plasma showed that the dendrimers provided sequential release of the two model drugs, with BA being released faster than PPA from all of the dendrons. The different dendrimers allowed delivery of increasing amounts (0.15–0.30 mM) and in exact molecular ratios (1:2; 2:1; 1:2; 2:2) of the two model drug compounds. The dendrimers were noncytotoxic (100% viability at 1 mg/mL) toward human umbilical vein endothelial cells (HUVEC) and nontoxic toward red blood cells, as confirmed by hemolysis studies. These studies demonstrate that these Janus PEG-based dendrimers offer great potential for the delivery of drugs via combination therapy.

Electrical stimulation for trunk control in paraplegia:A feasibility study

Paraplegic subjects lack trunk stability due to the loss of voluntary muscle control.This leads to a restriction of the volume of bi-manual workspace available,and hence has a detrimental impact on activities of daily living. Electrical Stimulation of paralysed muscles can be used to stabilize the trunk, but has never been applied in closed loop for this purpose. This paper describes the development of two closed loop controllers(PID and LQR),and their experimental evaluation on a human subject. Advantages and disadvantages of the two are discussed,considering a potential use of this technology during daily activities.

Volatile isoprenoid emissions from plastid to planet

Approximately 1–2% of net primary production by land plants is re-emitted to the atmosphere as isoprene and monoterpenes. These emissions play major roles in atmospheric chemistry and air pollution–climate interactions. Phenomenological models have been developed to predict their emission rates, but limited understanding of the function and regulation of these emissions has led to large uncertainties in model projections of air quality and greenhouse gas concentrations. We synthesize recent advances in diverse fields, from cell physiology to atmospheric remote sensing, and use this information to propose a simple conceptual model of volatile isoprenoid emission based on regulation of metabolism in the chloroplast. This may provide a robust foundation for scaling up emissions from the cellular to the global scale.

Wave-breaking characteristics of Northern Hemisphere winter blocking: a two-dimensional approach

This paper generalises and applies recently developed blocking diagnostics in a two- dimensional latitude-longitude context, which takes into consideration both mid- and high-latitude blocking. These diagnostics identify characteristics of the associated wave-breaking as seen in the potential temperature (θ) on the dynamical tropopause, in particular the cyclonic or anticyclonic Direction of wave-Breaking (DB index), and the Relative Intensity (RI index) of the air masses that contribute to blocking formation. The methodology is extended to a 2-D domain and a cluster technique is deployed to classify mid- and high-latitude blocking according to the wave-breaking characteristics. Mid-latitude blocking is observed over Europe and Asia, where the meridional gradient of θ is generally weak, whereas high-latitude blocking is mainly present over the oceans, to the north of the jet-stream, where the meridional gradient of θ is much stronger. They occur respectively on the equatorward and poleward flank of the jet- stream, where the horizontal shear ∂u/∂y is positive in the first case and negative in the second case. A regional analysis is also conducted. It is found that cold-anticyclonic and cyclonic blocking divert the storm-track respectively to the south and to the north over the East Atlantic and western Europe. Furthermore, warm-cyclonic blocking over the Pacific and cold-anticyclonic blocking over Europe are identified as the most persistent types and are associated with large amplitude anomalies in temperature and precipitation. Finally, the high-latitude, cyclonic events seem to correlate well with low- frequency modes of variability over the Pacific and Atlantic Ocean.

Winter and Summer Northern Hemisphere blocking in CMIP5 models

The frequencies of atmospheric blocking in both winter and summer and the changes in them from the 20th to the 21st centuries as simulated in twelve CMIP5 models is analysed. The RCP 8.5 high emission scenario runs are used to represent the 21st century. The analysis is based on the wave-breaking methodology of Pelly and Hoskins (2003a). It differs from the Tibaldi and Molteni (1990) index in viewing equatorward cut-off lows and poleward blocking highs in equal manner as indicating a disruption to the westerlies. 1-dimensional and 2-dimensional diagnostics are applied to identify blocking of the mid-latitude storm-track and also at higher latitudes. Winter blocking frequency is found to be generally underestimated. The models give a decrease in the European blocking maximum in the 21st century, consistent with the results in other studies. There is a mean 21st century winter poleward shift of high- latitude blocking, but little agreement between the models on the details. In summer, Eurasian blocking is also underestimated in the models, whereas it is now too large over the high-latitude ocean basins. A decrease in European blocking frequency in the 21st century model runs is again found. However in summer there is a clear eastward shift of blocking over Eastern Europe and Western Russia, in a region close to the blocking that dominated the Russian summer of 2010. While summer blocking decreases in general, the poleward shift of the storm track into the region of frequent high latitude blocking may mean that the incidence of storms being obstructed by blocks may actually increase.

Enhancing fieldwork learning with technology: practitioner's perspectives

This research paper reports the findings from an international survey of fieldwork practitioners on their use of technology to enhance fieldwork teaching and learning. It was found that there was high information technology usage before and after time in the field, but some were also using portable devices such as smartphones and global positioning system whilst out in the field. The main pedagogic reasons cited for the use of technology were the need for efficient data processing and to develop students' technological skills. The influencing factors and barriers to the use of technology as well as the importance of emerging technologies are discussed.

Free People of Color: expulsion and enslavement in the Antebellum South

This chapter explores the expulsion and enslavement of free People of Color in the southern states of the USA before the Civil War.

Climate determinism revisited: multiple equilibria in a complex climate model

Multiple equilibria in a coupled ocean–atmosphere–sea ice general circulation model (GCM) of an aquaplanet with many degrees of freedom are studied. Three different stable states are found for exactly the same set of parameters and external forcings: a cold state in which a polar sea ice cap extends into the midlatitudes; a warm state, which is ice free; and a completely sea ice–covered “snowball” state. Although low-order energy balance models of the climate are known to exhibit intransitivity (i.e., more than one climate state for a given set of governing equations), the results reported here are the first to demonstrate that this is a property of a complex coupled climate model with a consistent set of equations representing the 3D dynamics of the ocean and atmosphere. The coupled model notably includes atmospheric synoptic systems, large-scale circulation of the ocean, a fully active hydrological cycle, sea ice, and a seasonal cycle. There are no flux adjustments, with the system being solely forced by incoming solar radiation at the top of the atmosphere. It is demonstrated that the multiple equilibria owe their existence to the presence of meridional structure in ocean heat transport: namely, a large heat transport out of the tropics and a relatively weak high-latitude transport. The associated large midlatitude convergence of ocean heat transport leads to a preferred latitude at which the sea ice edge can rest. The mechanism operates in two very different ocean circulation regimes, suggesting that the stabilization of the large ice cap could be a robust feature of the climate system. Finally, the role of ocean heat convergence in permitting multiple equilibria is further explored in simpler models: an atmospheric GCM coupled to a slab mixed layer ocean and an energy balance model

Ocean heat transport and water vapor greenhouse in a warm equable climate: a new look at the low gradient paradox

The authors study the role of ocean heat transport (OHT) in the maintenance of a warm, equable, ice-free climate. An ensemble of idealized aquaplanet GCM calculations is used to assess the equilibrium sensitivity of global mean surface temperature and its equator-to-pole gradient (ΔT) to variations in OHT, prescribed through a simple analytical formula representing export out of the tropics and poleward convergence. Low-latitude OHT warms the mid- to high latitudes without cooling the tropics; increases by 1°C and ΔT decreases by 2.6°C for every 0.5-PW increase in OHT across 30° latitude. This warming is relatively insensitive to the detailed meridional structure of OHT. It occurs in spite of near-perfect atmospheric compensation of large imposed variations in OHT: the total poleward heat transport is nearly fixed. The warming results from a convective adjustment of the extratropical troposphere. Increased OHT drives a shift from large-scale to convective precipitation in the midlatitude storm tracks. Warming arises primarily from enhanced greenhouse trapping associated with convective moistening of the upper troposphere. Warming extends to the poles by atmospheric processes even in the absence of high-latitude OHT. A new conceptual model for equable climates is proposed, in which OHT plays a key role by driving enhanced deep convection in the midlatitude storm tracks. In this view, the climatic impact of OHT depends on its effects on the greenhouse properties of the atmosphere, rather than its ability to increase the total poleward energy transport.

The role of oceans and sea ice in abrupt transitions between multiple climate states

The coupled climate dynamics underlying large, rapid, and potentially irreversible changes in ice cover are studied. A global atmosphere–ocean–sea ice general circulation model with idealized aquaplanet geometry is forced by gradual multi-millennial variations in solar luminosity. The model traverses a hysteresis loop between warm ice-free conditions and cold glacial conditions in response to ±5 W m−2 variations in global, annual-mean insolation. Comparison of several model configurations confirms the importance of polar ocean processes in setting the sensitivity and time scales of the transitions. A “sawtooth” character is found with faster warming and slower cooling, reflecting the opposing effects of surface heating and cooling on upper-ocean buoyancy and, thus, effective heat capacity. The transition from a glacial to warm, equable climate occurs in about 200 years. In contrast to the “freshwater hosing” scenario, transitions are driven by radiative forcing and sea ice feedbacks. The ocean circulation, and notably the meridional overturning circulation (MOC), does not drive the climate change. The MOC (and associated heat transport) collapses poleward of the advancing ice edge, but this is a purely passive response to cooling and ice expansion. The MOC does, however, play a key role in setting the time scales of the transition and contributes to the asymmetry between warming and cooling.

Opening up climate research: A linked data approach to publishing data provenance

Traditionally, the formal scientific output in most fields of natural science has been limited to peer- reviewed academic journal publications, with less attention paid to the chain of intermediate data results and their associated metadata, including provenance. In effect, this has constrained the representation and verification of the data provenance to the confines of the related publications. Detailed knowledge of a dataset’s provenance is essential to establish the pedigree of the data for its effective re-use, and to avoid redundant re-enactment of the experiment or computation involved. It is increasingly important for open-access data to determine their authenticity and quality, especially considering the growing volumes of datasets appearing in the public domain. To address these issues, we present an approach that combines the Digital Object Identifier (DOI) – a widely adopted citation technique – with existing, widely adopted climate science data standards to formally publish detailed provenance of a climate research dataset as an associated scientific workflow. This is integrated with linked-data compliant data re-use standards (e.g. OAI-ORE) to enable a seamless link between a publication and the complete trail of lineage of the corresponding dataset, including the dataset itself.

A new scenario framework for climate change research: background, process, and future directions

The scientific community is developing new global, regional, and sectoral scenarios to facilitate interdisciplinary research and assessment to explore the range of possible future climates and related physical changes that could pose risks to human and natural systems; how these changes could interact with social, economic, and environmental development pathways; the degree to which mitigation and adaptation policies can avoid and reduce risks; the costs and benefits of various policy mixes; residual impacts under alternative pathways; and the relationship of future climate change and adaptation and mitigation policy responses with sustainable development. This paper provides the background to and process of developing the conceptual framework for these scenarios, as described in the three subsequent papers in this Special Issue (Van Vuuren et al.; O’Neill et al.; Kriegler et al.). The paper also discusses research needs to further develop and apply this framework. A key goal of the current framework design and its future development is to facilitate the collaboration of climate change researchers from a broad range of perspectives and disciplines to develop policy- and decision-relevant scenarios and explore the challenges and opportunities human and natural systems could face with additional climate change.

ENSO impact on Kelvin waves and associated tropical convection

The impact of El Nino–Southern Oscillation (ENSO) on atmospheric Kelvin waves and associated tropical convection is investigated using the ECMWF Re-Analysis, NOAA outgoing longwave radiation (OLR), and the analysis technique introduced in a previous study. It is found that the phase of ENSO has a substantial impact on Kelvin waves and associated convection over the equatorial central-eastern Pacific. El Nino (La Nina) events enhance (suppress) variability of the upper-tropospheric Kelvin wave and the associated convection there, both in extended boreal winter and summer. The mechanism of the impact is through changes in the ENSO-related thermal conditions and the ambient flow. In El Nino years, because of SST increase in the equatorial central-eastern Pacific, variability of eastward-moving convection, which is mainly associated with Kelvin waves, intensifies in the region. In addition, owing to the weakening of the equatorial eastern Pacific westerly duct in the upper troposphere in El Nino years, Kelvin waves amplify there. In La Nina years, the opposite occurs. However, the stronger westerly duct in La Nina winters allows more NH extratropical Rossby wave activity to propagate equatorward and force Kelvin waves around 200 hPa, partially offsetting the in situ weakening effect of the stronger westerlies on the waves. In general, in El Nino years Kelvin waves are more convectively and vertically coupled and propagate more upward into the lower stratosphere over the central-eastern Pacific. The ENSO impact in other regions is not clear, although in winter over the eastern Indian and western Pacific Oceans Kelvin waves and their associated convection are slightly weaker in El Nino than in La Nina years.