On the threshold energization of radiation belt electrons by double layers

Using a Hamiltonian approach, we quantify the energization threshold of electrons interacting with radiation belts' double layers discovered by Mozer et al. (2013). We find that double layers with electric field amplitude E0 ranging between 10 and 100 mV/m and spatial scales of the order of few Debye lengths are very efficient in energizing electrons with initial velocities v∥ ≤ vth to 1 keV levels but are unable to energize electrons with E ≥ 100 keV. Our results indicate that the localized electric field associated with the double layers are unlikely to generate a seed population of 100 keV necessary for a plethora of relativistic acceleration mechanisms and additional transport to higher energetic levels.Peer reviewe

Effects of solar wind magnetosphere coupling recorded at different geomagnetic latitudes: Separation of directly-driven and storage/release systems

The effect on geomagnetic activity of solar wind speed, compared with that of the strength of the interplanetary magnetic field, differs with geomagnetic latitude. In this study we construct a new index based on monthly standard deviations in the H-component of the geomagnetic field for all geomagnetic latitudes. We demonstrate that for this index the response at auroral regions correlates best with interplanetary coupling functions which include the solar wind speed while mid- and low-latitude regions respond to variations in the interplanetary magnetic field strength. These results are used to isolate the responsible geomagnetic current systems

Relation between substorm characteristics and rapid temporal variations of the ground magnetic field

Auroral substorms are one of the major causes of large geomagnetically induced currents (GIC) in technological systems. This study deals with different phases of the auroral substorm concerning their severity from the GIC viewpoint. Our database consists of 833 substorms observed by the IMAGE magnetometer network in 1997 (around sunspot minimum) and 1999 (rising phase of the sunspot cycle), divided into two classes according to the <i>D<sub>st</sub></i> index: non-storm (<i>D<sub>st</sub></i>>-40 nT, 696 events) and storm-time ones (<i>D<sub>st</sub></i><-40 nT, 137 events). The key quantity concerning GIC is the time derivative of the horizontal magnetic field vector (<i>d</i><i><b>H</b></i>/<i>dt</i>) whose largest values during substorms occur most probably at about 5 min after the onset at stations with CGM latitude less than 72 deg. When looking at the median time of the occurrence of the maximum <i>d</i><i><b>H</b></i>/<i>dt</i> after the expansion onset, it increases as a function of latitude from about 15 min at CGM lat=56 deg to about 45 min at CGM lat=75 deg for non-storm substorms. For storm-time events, these times are about 5 min longer. Based on calculated ionospheric equivalent currents, large <i>d</i><i><b>H</b></i>/<i>dt</i> occur mostly during the substorm onset when the amplitude of the westward electrojet increases rapidly

Target-specific compound selectivity for multi-target drug discovery and repurposing

Most drug molecules modulate multiple target proteins, leading either to therapeutic effects or unwanted side effects. Such target promiscuity partly contributes to high attrition rates and leads to wasted costs and time in the current drug discovery process, and makes the assessment of compound selectivity an important factor in drug development and repurposing efforts. Traditionally, selectivity of a compound is characterized in terms of its target activity profile (wide or narrow), which can be quantified using various statistical and information theoretic metrics. Even though the existing selectivity metrics are widely used for characterizing the overall selectivity of a compound, they fall short in quantifying how selective the compound is against a particular target protein (e.g., disease target of interest). We therefore extended the concept of compound selectivity towards target-specific selectivity, defined as the potency of a compound to bind to the particular protein in comparison to the other potential targets. We decompose the target-specific selectivity into two components: 1) the compound's potency against the target of interest (absolute potency), and 2) the compound's potency against the other targets (relative potency). The maximally selective compound-target pairs are then identified as a solution of a bi-objective optimization problem that simultaneously optimizes these two potency metrics. In computational experiments carried out using large-scale kinase inhibitor dataset, which represents a wide range of polypharmacological activities, we show how the optimization-based selectivity scoring offers a systematic approach to finding both potent and selective compounds against given kinase targets. Compared to the existing selectivity metrics, we show how the target-specific selectivity provides additional insights into the target selectivity and promiscuity of multi-targeting kinase inhibitors. Even though the selectivity score is shown to be relatively robust against both missing bioactivity values and the dataset size, we further developed a permutation-based procedure to calculate empirical p-values to assess the statistical significance of the observed selectivity of a compound-target pair in the given bioactivity dataset. We present several case studies that show how the target-specific selectivity can distinguish between highly selective and broadly-active kinase inhibitors, hence facilitating the discovery or repurposing of multi-targeting drugs.Peer reviewe

Contribution of magnetotail reconnection to the cross-polar cap electric potential drop

Since the work of Dungey (1961), the global circulation pattern with two (dayside and nightside) reconnection regions has become a classic concept. However, the contributions of dayside and nightside sources to the cross-polar cap potential (PCP) are not fully understood, particularly, the relative role and specifics of the nightside source are poorly investigated both in quantitative and qualitative terms. To fill this gap, we address the contributions of dayside and nightside sources to the PCP by conducting global MHD simulations with both idealized solar wind input and an observed event input. The dayside source was parameterized by solar wind–based “dayside merging potential” Φd = LeffVBt sin4(θ/2), whereas to characterize the nightside source we integrated across the tail the dawn-dusk electric field in the plasma sheet (to obtain the “cross-tail potential” Φn). For the idealized run we performed simulations using four MHD codes available at the Community Coordinated Modeling Center to show that contribution of the nightside source is a code-independent feature (although there are many differences in the outputs provided by different codes). Particularly, we show that adding a nightside source to the linear fit function for the ionospheric potential (i.e., using the fit function Φfit = KdΦd + KnΦn + Φ0) considerably improves the fitting results both in the idealized events as well as in the simulation of an observed event. According to these simulations the nightside source contribution to the PCP has a fast response time (<5 min) and a modest efficiency (potential transmission factor from tail to the ionosphere is small, Kn < 0.2), which is closely linked to the primarily inductive character of strong electric field generated in the plasma sheet. The latter time intervals are marked by strongly enhanced nightside (lobe) reconnection and can be associated with substorm expansion phases. This association is further strengthened by the simulated patterns of precipitation, the R1-type field-aligned substorm current wedge currents and Hall electrojet currents, which are consistent with the known substorm signatures

Substorm occurrence during quiet solar wind driving

Peer reviewe

A statistical study of magnetic field fluctuations in the dayside magnetosheath and their dependence on upstream solar wind conditions

The magnetosheath functions as a natural interface connecting the interplanetary and magnetospheric plasma. Since the magnetosheath houses the shocked solar wind, it is populated with abundant magnetic field turbulence which are generated both locally and externally. Although the steady state magnetosheath is to date relatively well understood, the same cannot be said of transient magnetic perturbations due to their kinetic nature and often complex and numerous generation mechanisms. The current manuscript presents a statistical study of magnetic field fluctuations in the dayside magnetosheath as a function of upstream solar wind conditions. We concentrate on the ambient higher-frequency fluctuations in the range of 0.1 Hz -> 2 Hz. We show evidence that the dawn (quasi-parallel) flank is visibly prone to higher-amplitude magnetic perturbations compared to the dusk (quasi-perpendicular) region. Our statistical data also suggest that the magnitude of turbulence can be visibly enhanced close to the magnetopause during periods of southward interplanetary magnetic field orientations. Faster (> 400 km s−1) solar wind velocities also appear to drive higher-amplitude perturbations compared to slower speeds. The spatial distribution also suggests some dependence on the magnetic pileup region at the subsolar magnetopause.Peer reviewe

Coronal mass ejections and their sheath regions in interplanetary space

Interplanetary coronal mass ejections (ICMEs) are large-scale heliospheric transients that originate from the Sun. When an ICME is sufficiently faster than the preceding solar wind, a shock wave develops ahead of the ICME. The turbulent region between the shock and the ICME is called the sheath region. ICMEs and their sheaths and shocks are all interesting structures from the fundamental plasma physics viewpoint. They are also key drivers of space weather disturbances in the heliosphere and planetary environments. ICME-driven shock waves can accelerate charged particles to high energies. Sheaths and ICMEs drive practically all intense geospace storms at the Earth, and they can also affect dramatically the planetary radiation environments and atmospheres. This review focuses on the current understanding of observational signatures and properties of ICMEs and the associated sheath regions based on five decades of studies. In addition, we discuss modelling of ICMEs and many fundamental outstanding questions on their origin, evolution and effects, largely due to the limitations of single spacecraft observations of these macro-scale structures. We also present current understanding of space weather consequences of these large-scale solar wind structures, including effects at the other Solar System planets and exoplanets. We specially emphasize the different origin, properties and consequences of the sheaths and ICMEs.Interplanetary coronal mass ejections (ICMEs) are large-scale heliospheric transients that originate from the Sun. When an ICME is sufficiently faster than the preceding solar wind, a shock wave develops ahead of the ICME. The turbulent region between the shock and the ICME is called the sheath region. ICMEs and their sheaths and shocks are all interesting structures from the fundamental plasma physics viewpoint. They are also key drivers of space weather disturbances in the heliosphere and planetary environments. ICME-driven shock waves can accelerate charged particles to high energies. Sheaths and ICMEs drive practically all intense geospace storms at the Earth, and they can also affect dramatically the planetary radiation environments and atmospheres. This review focuses on the current understanding of observational signatures and properties of ICMEs and the associated sheath regions based on five decades of studies. In addition, we discuss modelling of ICMEs and many fundamental outstanding questions on their origin, evolution and effects, largely due to the limitations of single spacecraft observations of these macro-scale structures. We also present current understanding of space weather consequences of these large-scale solar wind structures, including effects at the other Solar System planets and exoplanets. We specially emphasize the different origin, properties and consequences of the sheaths and ICMEs.Interplanetary coronal mass ejections (ICMEs) are large-scale heliospheric transients that originate from the Sun. When an ICME is sufficiently faster than the preceding solar wind, a shock wave develops ahead of the ICME. The turbulent region between the shock and the ICME is called the sheath region. ICMEs and their sheaths and shocks are all interesting structures from the fundamental plasma physics viewpoint. They are also key drivers of space weather disturbances in the heliosphere and planetary environments. ICME-driven shock waves can accelerate charged particles to high energies. Sheaths and ICMEs drive practically all intense geospace storms at the Earth, and they can also affect dramatically the planetary radiation environments and atmospheres. This review focuses on the current understanding of observational signatures and properties of ICMEs and the associated sheath regions based on five decades of studies. In addition, we discuss modelling of ICMEs and many fundamental outstanding questions on their origin, evolution and effects, largely due to the limitations of single spacecraft observations of these macro-scale structures. We also present current understanding of space weather consequences of these large-scale solar wind structures, including effects at the other Solar System planets and exoplanets. We specially emphasize the different origin, properties and consequences of the sheaths and ICMEs.Peer reviewe

Multiobjective optimization identifies cancer-selective combination therapies

Author summary Cancer is diagnosed in nearly 40% of people in the U.S at some point during their lifetimes. Despite decades of research to lower cancer incidence and mortality, cancer remains a leading cause of deaths worldwide. Therefore, new targeted therapies are required to further reduce the death rates and toxic effects of treatments. Here we developed a mathematical optimization framework for finding cancer-selective treatments that optimally use drugs and their combinations. The method uses multiobjective optimization to identify drug combinations that simultaneously show maximal therapeutic potential and minimal non-selectivity, to avoid severe side effects. Our systematic search approach is applicable to various cancer types and it enables optimization of combinations involving both targeted therapies as well as standard chemotherapies. Combinatorial therapies are required to treat patients with advanced cancers that have become resistant to monotherapies through rewiring of redundant pathways. Due to a massive number of potential drug combinations, there is a need for systematic approaches to identify safe and effective combinations for each patient, using cost-effective methods. Here, we developed an exact multiobjective optimization method for identifying pairwise or higher-order combinations that show maximal cancer-selectivity. The prioritization of patient-specific combinations is based on Pareto-optimization in the search space spanned by the therapeutic and nonselective effects of combinations. We demonstrate the performance of the method in the context of BRAF-V600E melanoma treatment, where the optimal solutions predicted a number of co-inhibition partners for vemurafenib, a selective BRAF-V600E inhibitor, approved for advanced melanoma. We experimentally validated many of the predictions in BRAF-V600E melanoma cell line, and the results suggest that one can improve selective inhibition of BRAF-V600E melanoma cells by combinatorial targeting of MAPK/ERK and other compensatory pathways using pairwise and third-order drug combinations. Our mechanism-agnostic optimization method is widely applicable to various cancer types, and it takes as input only measurements of a subset of pairwise drug combinations, without requiring target information or genomic profiles. Such data-driven approaches may become useful for functional precision oncology applications that go beyond the cancer genetic dependency paradigm to optimize cancer-selective combinatorial treatments.Peer reviewe

Auroral electrojets during deep solar minimum at the end of solar cycle 23

We investigate the auroral electrojet activity during the deep minimum at the end of solar cycle 23 (2008–2009) by comparing data from the IMAGE magnetometer chain, auroral observations in Fennoscandia and Svalbard, and solar wind and interplanetary magnetic field (IMF) observations from the OMNI database from that period with those recorded one solar cycle earlier. We examine the eastward and westward electrojets and the midnight sector separately. The electrojets during 2008–2009 were found to be weaker and at more poleward latitudes than during other times, but when similar driving solar wind and IMF conditions are compared, the behavior in the morning and evening sectors during 2008–2009 was similar to other periods. On the other hand, the midnight sector shows distinct behavior during 2008–2009: for similar driving conditions, the electrojets resided at further poleward latitudes and on average were weaker than during other periods. Furthermore, the substorm occurrence frequency seemed to saturate to a minimum level for very low levels of driving during 2009. This analysis suggests that the solar wind coupling to the ionosphere during 2008–2009 was similar to other periods but that the magnetosphere-ionosphere coupling has features that are unique to this period of very low solar activity.Peer reviewe