Abstract
Hailstorms pose a significant socioeconomic risk, necessitating detailed assessments of how the hail threat changes throughout their lifetimes. Hail production involves the favorable ...juxtaposition of ingredients, but how storm evolution affects these ingredients is unknown, limiting understanding of how hail production evolves. Unfortunately, neither surface hail reports nor radar-based swath estimates have adequate resolution or details needed to assess evolving hail production. Instead, we use a novel approach of coupling a detailed hail trajectory model to idealized convective storm simulations to better understand storm evolution’s influence on hail production. Hail production varies substantially throughout storms’ mature phases: maximum sizes vary by a factor of two, and the concentration of severe hail more than fivefold during 45-60-min periods. This variability arises from changes in updraft properties, which come from (i) changes in low-level convergence, and (ii) internal storm dynamics, including anticyclonic vortex shedding/storm splitting, and the response of the updraft’s airflow and supercooled liquid water content to these events. Hodograph shape strongly affects such behaviors. Straighter hodographs lead to more prolific hail production through wider updrafts and weaker mesocyclones, and a periodicity in hail size metrics associated with anticyclonic vortex shedding and/or storm splitting. In contrast, a curved hodograph (favorable for tornadoes) led to a storm with a stronger but more compact updraft, which occasionally produced giant (10-cm) hail, but that was a less-prolific severe hail producer overall. Unless storms are adequately sampled throughout their lifecycles, snapshots from ground reports will insufficiently resolve the true nature of hail production.
We present herein a compilation and trend analysis of human i.v. pharmacokinetic data on 670 drugs representing, to our knowledge, the largest publicly available set of human clinical pharmacokinetic ...data. This data set provides the drug metabolism scientist with a robust and accurate resource suitable for a number of applications, including in silico modeling, in vitro-in vivo scaling, and physiologically based pharmacokinetic approaches. Clearance, volume of distribution at steady state, mean residence time, and terminal phase half-life were obtained or derived from original references exclusively from studies utilizing i.v. administration. Plasma protein binding data were collected from other sources to supplement these pharmacokinetic data. These parameters were analyzed concurrently with a range of simple physicochemical descriptors, and resultant trends and patterns within the data are presented. Our findings with this much expanded data set were consistent with earlier described notions of trends between physicochemical properties and pharmacokinetic behavior. These observations and analyses, along with the large database of human pharmacokinetic data, should enable future efforts aimed toward developing quantitative structure-pharmacokinetic relationships and improving our understanding of the relationship between fundamental chemical characteristics and drug disposition.
Several technical modifications have been described to avoid complications of venous flaps. The authors describe a technical variation of the venous flap to reduce the risk of venous congestion and ...the likelihood of shunting, thus increasing venous flap reliability.
Targeted genome editing in hematopoietic stem/progenitor cells (HSPCs) is an attractive strategy for treating immunohematological diseases. However, the limited efficiency of homology-directed ...editing in primitive HSPCs constrains the yield of corrected cells and might affect the feasibility and safety of clinical translation. These concerns need to be addressed in stringent preclinical models and overcome by developing more efficient editing methods. We generated a humanized X-linked severe combined immunodeficiency (SCID-X1) mouse model and evaluated the efficacy and safety of hematopoietic reconstitution from limited input of functional HSPCs, establishing thresholds for full correction upon different types of conditioning. Unexpectedly, conditioning before HSPC infusion was required to protect the mice from lymphoma developing when transplanting small numbers of progenitors. We then designed a one-size-fits-all
(interleukin-2 receptor common γ-chain) gene correction strategy and, using the same reagents suitable for correction of human HSPC, validated the edited human gene in the disease model in vivo, providing evidence of targeted gene editing in mouse HSPCs and demonstrating the functionality of the
-edited lymphoid progeny. Finally, we optimized editing reagents and protocol for human HSPCs and attained the threshold of
editing in long-term repopulating cells predicted to safely rescue the disease, using clinically relevant HSPC sources and highly specific zinc finger nucleases or CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9). Overall, our work establishes the rationale and guiding principles for clinical translation of SCID-X1 gene editing and provides a framework for developing gene correction for other diseases.
Abstract The bearing capacity - the ability of a surface to support applied loads - is an important parameter for understanding and predicting the response of a surface. Previous work has inferred ...the bearing capacity and trafficability of specific regions of the Moon using orbital imagery and measurements of the boulder tracks visible on its surface. Here, we estimate the bearing capacity of the surface of an asteroid for the first time using DART/DRACO images of suspected boulder tracks on the surface of asteroid (65803) Didymos. Given the extremely low surface gravity environment, special attention is paid to the underlying assumptions of the geotechnical approach. The detailed analysis of the boulder tracks indicates that the boulders move from high to low gravitational potential, and provides constraints on whether the boulders may have ended their surface motion by entering a ballistic phase. From the 9 tracks identified with sufficient resolution to estimate their dimensions, we find an average boulder track width and length of 8.9 $$\pm$$ ± 1.5 m and 51.6 $$\pm$$ ± 13.3 m, respectively. From the track widths, the mean bearing capacity of Didymos is estimated to be 70 N/m 2 , implying that every 1 m 2 of Didymos’ surface at the track location can support only ~70 N of force before experiencing general shear failure. This value is at least 3 orders of magnitude less than the bearing capacity of dry sand on Earth, or lunar regolith.
Functional Connectivity (FC) during resting-state or task conditions is not static but inherently dynamic. Yet, there is no consensus on whether fluctuations in FC may resemble isolated transitions ...between discrete FC states rather than continuous changes. This quarrel hampers advancing the study of dynamic FC. This is unfortunate as the structure of fluctuations in FC can certainly provide more information about developmental changes, aging, and progression of pathologies. We merge the two perspectives and consider dynamic FC as an ongoing network reconfiguration, including a stochastic exploration of the space of possible steady FC states. The statistical properties of this random walk deviate both from a purely “order-driven” dynamics, in which the mean FC is preserved, and from a purely “randomness-driven” scenario, in which fluctuations of FC remain uncorrelated over time. Instead, dynamic FC has a complex structure endowed with long-range sequential correlations that give rise to transient slowing and acceleration epochs in the continuous flow of reconfiguration. Our analysis for fMRI data in healthy elderly revealed that dynamic FC tends to slow down and becomes less complex as well as more random with increasing age. These effects appear to be strongly associated with age-related changes in behavioural and cognitive performance.
•Dynamic Functional Connectivity (dFC) at rest and during cognitive task performs a “complex” (anomalous) random walk.•Speed of dFC slows down with aging.•Resting dFC replaces complexity by randomness with aging.•Task performance correlates with the speed and complexity of dFC.
Complex hydrides for energy storage Milanese, C.; Jensen, T.R.; Hauback, B.C. ...
International journal of hydrogen energy,
03/2019, Letnik:
44, Številka:
15
Journal Article
Recenzirano
Odprti dostop
In the past decades, complex hydrides and complex hydrides-based materials have been thoroughly investigated as materials for energy storage, owing to their very high gravimetric and volumetric ...hydrogen capacities and interesting cation and hydrogen diffusion properties. Concerning hydrogen storage, the main limitations of this class of materials are the high working temperatures and pressures, the low hydrogen absorption and desorption rates and the poor cyclability. In the past years, research in this field has been focused on understanding the hydrogen release and uptake mechanism of the pristine and catalyzed materials and on the characterization of the thermodynamic aspects, in order to rationally choose the composition and the stoichiometry of the systems in terms of hydrogen active phases and catalysts/destabilizing agents. Moreover, new materials have been discovered and characterized in an attempt to find systems with properties suitable for practical on-board and stationary applications. A significant part of this rich and productive activity has been performed by the research groups led by the Experts of the International Energy Agreement Task 32, often in collaborative research projects. The most recent findings of these joint activities and other noteworthy recent results in the field are reported in this paper.
•New borohydrides are described concerning the chemical and structural properties.•The H2 mechanism in innovative RHCs and the use of original catalysts are evidenced.•The ionic liquids' action on H2 production and release by borohydrides is detailed.•The use of metal hydrides as catalysts for (de)hydrogenation reactions is explored.•Original solubility data in hydrides systems in solid and liquid state are presented.
Intracellular cargo transport relies on myosin Va molecular motor ensembles to travel along the cell's three-dimensional (3D) highway of actin filaments. At actin filament intersections, the ...intersecting filament is a structural barrier to and an alternate track for directed cargo transport. Here we use 3D super-resolution fluorescence imaging to determine the directional outcome (that is, continues straight, turns or terminates) for an ∼10 motor ensemble transporting a 350 nm lipid-bound cargo that encounters a suspended 3D actin filament intersection in vitro. Motor-cargo complexes that interact with the intersecting filament go straight through the intersection 62% of the time, nearly twice that for turning. To explain this, we develop an in silico model, supported by optical trapping data, suggesting that the motors' diffusive movements on the vesicle surface and the extent of their engagement with the two intersecting actin tracks biases the motor-cargo complex on average to go straight through the intersection.
Mastocytosis and allergic diseases Bonadonna, P; Lombardo, C; Zanotti, R
Journal of investigational allergology & clinical immunology,
2014, Letnik:
24, Številka:
5
Journal Article
Recenzirano
Mastocytosis is a clonal disorder characterized by proliferation and accumulation of mast cells in various tissues, mainly skin and bone marrow. It can cause a wide variety of clinical ...manifestations-other than urticaria pigmentosa-that can lead to inappropriate release of mediators by mast cells. The most severe manifestation is anaphylaxis. The triggers of anaphylaxis in adults with mastocytosis are numerous, but Hymenoptera stings seem to be the most frequent, followed by foods and drugs. Therefore, to prevent severe reactions, it is very important to recognize and avoid potential triggers; in addition, venom-allergic patients must receive lifelong immunotherapy, which has proven very effective. Given that published data on drug anaphylaxis in patients with mast cell disorders are scarce, it is not currently possible to provide clear recommendations. The risk of systemic reactions during general anesthesia can be reduced by assessing risk on an individual basis (previous reaction to a drug or reaction during surgery) and by avoiding specific trigger factors (patient temperature changes, infusion of cold solution, tissue trauma, friction, and other mechanical factors).
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