Miracle-dz/UniFAR-FTUs huggingface dataset:
Utilizing an acute hyperthermia-induced seizure test and pharmacokinetic studies to establish optimal dosing regimens in a mouse model of Dravet syndrome

Objective The current standard of care for Dravet Syndrome includes polytherapy after inadequate seizure control with one or more monotherapy approaches. Treatment guidelines are often based on expert opinions, and finding an optimal balance between seizure control and adverse drug effects can be challenging. This study utilizes efficacy and pharmacokinetic analysis of a second-line treatment regimen that combines clobazam and sodium valproate with an add-on drug as a proof-of-principle approach to establish an effective therapeutic regimen in a preclinical mouse model of Dravet Syndrome. Method We evaluated the efficacy of add-on therapies stiripentol, cannabidiol, lorcaserin, or fenfluramine to clobazam and sodium valproate against hyperthermia-induced seizures in Scn1aA1783V/WT mice. Clobazam, N-desmethyl clobazam (an active metabolite of clobazam), sodium valproate, stiripentol, and cannabidiol concentrations were quantified in plasma and brain using liquid chromatography-tandem mass spectrometry for the combinations deemed effective against hyperthermia-induced seizures. The concentration data were used to calculate pharmacokinetic parameters via non-compartmental analysis in Phoenix WinNonLin. Results Higher doses of stiripentol or cannabidiol, in combination with clobazam and sodium valproate, were effective against hyperthermia-induced seizures in Scn1aA1783V/WT mice. In Scn1aWT/WT mice, brain clobazam and N-desmethyl clobazam concentrations were higher in the triple-drug combinations than in the clobazam monotherapy. Stiripentol and cannabidiol brain concentrations were greater in the triple-drug therapy than when given alone. Interpretation A polypharmacy strategy may be a practical preclinical approach to identifying efficacious compounds for Dravet Syndrome. The drug-drug interactions between compounds used in this study may explain the potentiated efficacy of some combination therapies. Graphical Abstract Key findings The hyperthermia-induced seizure assay in Scn1aA1783V/WT mice can identify efficacious antiseizure medications. A triple-drug administration paradigm was designed that mimics clinical standards for add-on therapies in DS. Stiripentol and cannabidiol were effective against hyperthermia-induced seizures when co-administered with clobazam and sodium valproate. Potential drug-drug interactions between compounds may explain the potentiated antiseizure effect in triple-drug therapies. The triple-drug “add-on” therapy approach may be a valuable preclinical strategy for screening investigational compounds for DS, an assay offered at the ETSP.
PROTOSPACEJAM: AN OPEN-SOURCE, CUSTOMIZABLE AND WEB-ACCESSIBLE DESIGN PLATFORM FOR CRISPR/CAS9 INSERTIONAL KNOCK-IN

CRISPR/Cas9-mediated knock-in of DNA sequences enables precise genome engineering for research and therapeutic applications. However, designing effective guide RNAs (gRNAs) and homology-directed repair (HDR) donors remains a bottleneck. Here, we present protoSpaceJAM, an open-source algorithm to automate and optimize gRNA and HDR donor design for CRISPR/Cas9 insertional knock-in experiments. protoSpaceJAM utilizes biological rules to rank gRNAs based on specificity, distance to insertion site, and position relative to regulatory regions. protoSpaceJAM can introduce recoding mutations (silent mutations and mutations in non-coding sequences) in HDR donors to prevent re-cutting and increase knock-in efficiency. Users can customize parameters and design double-stranded or single-stranded donors. We validated protoSpaceJAM’s design rules by demonstrating increased knock-in efficiency with recoding mutations and optimal strand selection for single-stranded donors. An additional module enables the design of genotyping primers for next-generation sequencing of edited alleles. Overall, protoSpaceJAM streamlines and optimizes CRISPR knock-in experimental design in a flexible and modular manner to benefit diverse research and therapeutic applications. protoSpaceJAM is available open-source as an interactive web tool at protospacejam.czbiohub. org or as a standalone Python package at github.com/czbiohub-sf/protoSpaceJAM.
Bacteria face trade-offs in the decomposition of complex biopolymers

Although depolymerization of complex carbohydrates is a growth-limiting bottleneck for microbial decomposers, we still lack understanding about how the production of different types of extracellular enzymes affect individual microbes and in turn the performance of whole decomposer communities. In this work we use a theoretical model to evaluate the potential trade-offs faced by microorganisms in biopolymer decomposition which arise due to the varied biochemistry of different depolymerizing enzyme classes. We specifically consider two broad classes of depolymerizing extracellular enzymes, which are widespread across microbial taxa: exo-enzymes that cleave small units from the ends of polymer chains and endo-enzymes that act at random positions generating degradation products of varied sizes. Our results demonstrate a fundamental trade-off in the production of these enzymes which can be explained by intrinsically different temporal depolymerization dynamics. As a consequence, specialists that produce either exo- or only endo-enzymes limit their growth to high or low substrate conditions, respectively. Conversely, generalists that produce both enzymes in an optimal ratio expand their niche and benefit from the synergy between the two enzymes. Finally, our results show that, in spatially-explicit environments, consortia composed of endo- and exo-specialists can only exist under oligotrophic conditions. In summary, our analysis demonstrates that the (evolutionary or ecological) selection of a depolymerization pathway will affect microbial fitness under low- or high substrate conditions, with impacts on the ecological dynamics of microbial communities. It provides a possible explanation why many polysaccharide degraders in nature show the genetic potential to produce both of these enzyme classes.
A quantitative study of the proximity of satellite detected active fires to roads and rivers in the Brazilian tropical moist forest biome

The Brazilian tropical moist forest biome (BTMFB) is experiencing high rates of deforestation and fire. Previous studies indicate that the majority of fires occur close to roads, however they did not consider the network of unofficial roads and navigable rivers, nor inter-state and inter-annual variability. We examine 8 years of Moderate Resolution Imaging Spectroradiometer (MODIS) active fire detections and the cumulative frequency distribution of the distance of each detection to the closest official road, unofficial road, and navigable river bank. Approximately 50 and 95% of all MODIS active fire detections occurred within 1 and 10km respectively of a road or navigable river. Inter-state and inter-annual variations are discussed and linkages to expansion of the road network are suggested. Comparison of the distance distribution of the MODIS active fire detections and the distance distribution of a 0.5-km spaced geographic grid to the combined roads and navigable river network revealed significant differences for each state and for the BTMFB and indicate that the great majority of fires are anthropogenic. The results provide insights that may be useful for modelling the incidence of fire under future expansion of the Amazonian road network and increased river navigability.
Hydrological processes and streamflow in a lake dominated watercourse

This paper discusses results of a nested basin study investigating run‐off responses along the watercourse in a 137 km2 subarctic Canadian Shield watershed. Catchment areas contributing surface run‐off to the basin outlet shrink after a maximum during spring snowmelt because of storage demands in headwater wetlands and lakes. This decrease is significant as summer contributing areas to the basin outlet are only 4% the size of spring melt contributing areas. This reduction in contributing area and decrease in antecedent lake levels lead to a two order of magnitude decrease in run‐off ratios from spring snowmelt to midsummer. Furthermore, the attenuating influence of lakes on the run‐off hydrograph increases the opportunity for evaporative losses, which prevents small run‐off events from maintaining a measurable flood wave through the basin. The location at which a run‐off event is interrupted in the watercourse is a function of lake size relative to upstream run‐off inputs. Run‐off is more susceptible to evaporative losses in large receiving lakes where inflow per unit area is less. These processes cause intermittent streamflow through the basin. These results have repercussions for coupled atmospheric/hydrological models whose resolution is approaching the basin scale. The incorporation of lateral transfer schemes that encompass these processes and physiographic influences on streamflow response is encouraged. Copyright © 2006 Crown in the right of Canada. Published by John Wiley & Sons, Ltd.
FAULT‐GRADED BEDS INTERPRETED AS SEISMITES

SUMMARY Fault grading is expressed by a regular structural sequence of (from top) liquified zone, rubble zone and step-faulted zone, with gradational contacts between these zones and the bottom, but with a sharp boundary at the top. It is interpreted as an effect of strong earthquakes on gradationally compacted muds in quiet water basins. Fault-graded beds are geopetal and paleoslope criteria. If interpreted as seismites they may also be used as paleo-seismograms.
Exploring the evolution of a volcanic seismic swarm: The case of the 2000 Izu Islands swarm

The goal of this paper is to yield physical constrains on the nature and evolution of a seismic swarm by means of a quantitative stochastic modeling of earthquakes occurrence. With this purpose, we fit different stationary and nonstationary stochastic ETAS models to the Izu Islands seismic swarm occurred in 2000. We find that a nonstationary model with background activity and p‐value varying through time describes the observations better than other simpler ETAS models. The coherent fluctuations of these parameters and of the spatio‐temporal earthquake distribution are interpreted in terms of a magma/fluids source process that evolves through outbursts of activity superimposed to low frequency variations. The results obtained suggest that suitable nonstationary ETAS modeling can be very useful to characterize the nature of the swarm source, and it may provide the basis to build a quantitative tool for tracking in almost real‐time the evolution of a magma/fluids source.
Why did the Southern Gulf of California Rupture So Rapidly

Rifts in the interior of continents that evolve to form large oceans typically last for 30 to 80 m.y. and longer before complete rupture of the continent and onset of sea-floor spreading. A distinct style of rifts form along the active tectonic margins of continents, and these rifts more commonly form marginal seas and terranes or continental blocks or slivers that are ruptured away from their home continent. The Gulf of California and the Baja California microplate make up one of the best examples of the latter setting and processes. In the southern Gulf of California, sea-floor spreading commenced only ~6–10 m.y. after the formation of the oblique-divergent plate boundary at ca. 12.5 Ma. Three main factors caused this rapid rupture: (1) an inherited long, narrow belt of hot, weak crust from a volcanic arc that was active immediately before formation of the oblique-divergent plate boundary and that lay between two strong batholith belts; (2) relatively rapid plate motion resulting in high strain rates; and (3) a dominant role of strike-slip faulting in the highly oblique-divergent setting that formed large pull-apart basins with rapid and focused crustal thinning in a linked en-echelon system. Accentuating factor 1 is that the formation of slab windows associated with microplate capture west of the Baja California peninsula may have further weakened the crust. These causes of rapid rupture of continental lithosphere are mostly linked to the fact that the Gulf of California developed along a long-lived tectonically active margin of a continent with a convergent or oblique-convergent setting since at least the Jurassic, but not a margin that was thickened in a major contractional orogen. This combination of causes and factors suggests that rifts that form at active margins are fundamentally different than continental interior rifts, and that these differences can produce vastly different rifting histories. The formation and northwestward motion of the Baja California microplate also show that “terranes” formed in an obliquedivergent setting can form and move long distances over relatively short geologic time intervals. INTRODUCTION The rupture of continental lithosphere is one of the most fundamental tectonic processes. Complete rupture of a continent requires the familiar progression from early rifting to extreme continental lithosphere thinning to continental breakup that forms oceanic spreading in a nascent ocean (e.g., Veevers, 1981). The development of a rift, and whether it progresses to breakup, is mainly dependent on the thermal structure, crustal thickness, and crustal strength of the lithosphere when rifting begins (e.g., Buck, 2007), as well as forces at the base of the lithosphere and far-field plate interactions (Ziegler and
Efficiency comparison of conventional and digital soil mapping for updating soil maps

This study compared the efficiency of geostatistical digital soil mapping (DSM) with conventional soil mapping (CSM) for updating soil class and property maps of a cultivated peatland in the Netherlands. For digital soil class mapping, the generalized linear geostatistical model was used. Digital mapping of the soil organic matter (SOM) content and peat thickness was done by universal kriging. The conventional soil class map was created by free survey, while the property maps were created with the representative profile description (RPD) and map unit means (MUM) methods. For each method, we computed the effort invested in the mapping in terms of the sampling and cost densities. The accuracies of the created soil maps were estimated from independent probability sample data. The results showed that for DSM, the cost density could be reduced by a factor of three compared with CSM without compromising accuracy. The map purity of both maps was around 55%. For conventional soil property mapping, the MUM maps were more accurate than the RPD maps. For SOM, CSM-MUM (RMSE 7.5%) performed better than DSM (RMSE 12.1%), although accuracy differences were not significant. For peat thickness, DSM (RMSE 23.3 cm) performed slightly better than CSM-MUM (RMSE 24.9 cm). Despite the differences in accuracy being small, the digital soil property maps were produced more efficiently. The cost density was a factor of 3.5 smaller. We conclude that for updating conventional soil maps in the Dutch peatlands, geostatistical DSM can be more efficient, although not necessarily more accurate, than CSM.
Extension of the measurement range of electrical conductivity by time-domain reflectometry (TDR)

The electrical conductivity (EC) of a medium invaded by TDR sensors can be estimated from the impedance of a TDR reflectogram. Four categories of sensor were tested in salt solutions and the impedances of the TDR pulse wave were correlated to the EC of the solution. The relation between the impedance and EC over a wide range of conductivities is non-linear but stable. Second- to fourth-degree polynomials can extend the measurement range to 44 dS m -1 (equivalent to a NaCl concentration of 28 g l -1 or 0.48 N) and result in better prediction of the conductivities than linear relations. For automatic measurement of EC with a datalogger, the method of Giese and Tiemann (1975, Adv. Mol. Rel. Processes, 7: 45-59) gives accurate measurement of conductivities lower than 10 dS m -1 . Polynomial relations between EC and the datalogger's record provide an accurate estimate of the conductivity over a wide range. However, for both manual and automatic measurements, the sensors need to be calibrated individually. In particular, in the non-linear region, the differences between sensors are larger. Fortunately, the relation is sufficiently stable to eliminate significant error.
Diagnosing recent CO emissions and ozone evolution in East Asia using coordinated surface observations, adjoint inverse modeling, and MOPITT satellite data

Simultaneous ground-based measurements of ozone (O3) and carbon monoxide (CO) were conducted in March 2005 as part of the East Asian Regional Experi- ment (EAREX) 2005 under the umbrella of the Atmospheric Brown Clouds (ABC) project. Multiple air quality monitor- ing networks were integrated by performing intercomparison of individual calibration standards and measurement tech- niques to ensure comparability of ambient measurements, along with providing consistently high time-resolution mea- surements of O3 and CO at the surface sites in East Asia. Ambient data collected from eight surface stations were com- pared with simulation results obtained by a regional chem- istry transport model to infer recent changes in CO emissions from East Asia. Our inverse estimates of the CO emissions from China up to 2005 suggested an increase of 16% since 2001, in good agreement with the recent MOPITT satellite observations and the bottom-up estimates up to 2006. The O3 enhancement relative to CO in continental pollution plumes traversed in the boundary layer were examined as a function of transport time from the Asian continent to the western Pa- cific Ocean. The observed 1O3/1CO ratios show increasing tendency during eastward transport events due likely to en- route photochemical O3 formation, suggesting that East Asia is an important O3 source region during spring.
Seismic tomography study of a bottom simulating reflector off the South Shetland Islands (Antarctica)

Abstract Reflection tomography techniques have been applied to two multi-channel seismic profiles, acquired across the accretionary prism of the South Sheltand margin, in order to reconstruct the velocity field associated with gas hydrate and free gas layers in the sedimentary sequence. Data show the presence of a strong bottom simulating reflector (BSR), running along the slope in water depths ranging from 1000 to 4600 m, locally underlain by a weak normal polarity reflector about 80 ms deeper in the section. The analysis indicates a velocity trend from the sea floor to the BSR generally consistent with that of normally compacted marine sediments, with an abrupt decrement between the BSR and the underlying reflector, indicating the presence of free gas in the sediment pore spaces. The calculated thickness of this gas-bearing layer is approximately 50 m. Local increments of tomographic velocity above the BSR can be related either to gas hydrate abundances in normally compacted slope basin sediments or to overcompaction in accreted sediments, as imaged by the pre-stack depth migrated sections. We conclude that clathrates and free gas distribution on the South Shetland continental slope are strongly controlled by the structural setting of the accretionary prism, where faults act as conduits for migration of natural gas towards the surface. A brief description of the adopted tomography method is also presented.
Cloudiness over the contiguous United States: Contemporary changes observed using ground‐based and ISCCP D2 data

Comparisons of monthly daytime cloudiness time series of total cloud cover (TCL) and cloud types' occurrences between the ground‐based and International Satellite Cloud Climatology Project (ISCCP) D2 datasets were conducted over the contiguous United States. Despite its large bias (+6.7% to +20.8%), TCL in ISCCP D2 is highly correlated with the surface observations in all seasons. Close correspondence of seasonal and interannual variability between these two datasets is also seen in low stratiform and cirrus clouds. Reconstruction of these cloud characteristics using ISCCP data was performed for the 1990s when the Automated Surface Observation System (ASOS) implementation irreversibly broke the homogeneity of ground‐based cloudiness time series over the United States. Verification of reconstructed cloudiness characteristics was conducted using the independent in‐situ climatic variables such as diurnal temperature range and precipitation.
Microstructural features of albite porphyroblasts as indicators of sequential Barrovian metamorphic mineral growth in the Caledonides of the SW Scottish Highlands

Inclusion – porphyroblast and porphyroblast – porphyroblast relationships show that abundant albite in mica schists in the Caledonides of the SW Scottish Highlands are part of the Barrovian metamorphic assemblage. Growth early in the D2 deformational phase of porphyroblast cores followed the growth of Mn‐rich garnet but preceded the growth of porphyroblasts of the index mineral almandine. Two sets of inclusion trails in the albite correspond to the regionally expressed S1 and S2. Straight trails of muscovite, chlorite, quartz, epidote and the earliest growth of biotite make up S1. Crenulated trails express deformation of S1 early in D2 with muscovite, chlorite, biotite, quartz, epidote and the Mn‐rich garnet associated with the development of S2 crenulation cleavage. The geometries of these trails uniquely record early stages of D2 deformational history. An 0−3 growth is related to the temporal coincidence of the formation of S1–S2 crenulation cleavage hinges as favourable sites for nucleation and the release of large amounts of water from prograde reactions during tectonothermal reconstitution of first cycle immature sediments with a volcanic component. The main characteristics of the regionally expressed D2 schistosity were developed during the major grain coarsening that followed both albite and almandine porphyroblast growth. Essentially inclusion‐free An 4−19 rims grew on the inclusion‐containing cores in the almandine zone in the later stages of schistosity growth and unoriented porphyroblasts of muscovite, biotite and chlorite indicate that mineral growth extended from the later stages of D2 to post‐D2. Previous interpretations of the albite porphyroblast growth having been during D4 to post‐D4 contemporaneous with retrogression are inconsistent with the microstructural evidence.