Abstract
The Astropy Project supports and fosters the development of open-source and openly developed
Python
packages that provide commonly needed functionality to the astronomical community. A key ...element of the Astropy Project is the core package
astropy
, which serves as the foundation for more specialized projects and packages. In this article, we provide an overview of the organization of the Astropy project and summarize key features in the core package, as of the recent major release, version 2.0. We then describe the project infrastructure designed to facilitate and support development for a broader ecosystem of interoperable packages. We conclude with a future outlook of planned new features and directions for the broader Astropy Project.
Purpose
Ventricular–arterial (V–A) decoupling decreases myocardial efficiency and is exacerbated by tachycardia that increases static arterial elastance (Ea). We thus investigated the effects of ...heart rate (HR) reduction on Ea in septic shock patients using the beta-blocker esmolol. We hypothesized that esmolol improves Ea by positively affecting the tone of arterial vessels and their responsiveness to HR-related changes in stroke volume (SV).
Methods
After at least 24 h of hemodynamic optimization, 45 septic shock patients, with an HR ≥95 bpm and requiring norepinephrine to maintain mean arterial pressure (MAP) ≥65 mmHg, received a titrated esmolol infusion to maintain HR between 80 and 94 bpm. Ea was calculated as MAP/SV. All measurements, including data from right heart catheterization, echocardiography, arterial waveform analysis, and norepinephrine requirements, were obtained at baseline and at 4 h after commencing esmolol.
Results
Esmolol reduced HR in all patients and this was associated with a decrease in Ea (2.19 ± 0.77 vs. 1.72 ± 0.52 mmHg l
−1
), arterial d
P
/d
t
max
(1.08 ± 0.32 vs. 0.89 ± 0.29 mmHg ms
−1
), and a parallel increase in SV (48 ± 14 vs. 59 ± 18 ml), all
p
< 0.05. Cardiac output and ejection fraction remained unchanged, whereas norepinephrine requirements were reduced (0.7 ± 0.7 to 0.58 ± 0.5 µg kg
−1
min
−1
,
p
< 0.05).
Conclusions
HR reduction with esmolol effectively improved Ea while allowing adequate systemic perfusion in patients with severe septic shock who remained tachycardic despite standard volume resuscitation. As Ea is a major determinant of V–A coupling, its reduction may contribute to improving cardiovascular efficiency in septic shock.
The Kamchatka Peninsula in far eastern Russia represents the most volcanically active arc in the world in terms of magma production and the number of explosive eruptions. We investigate large-scale ...silicic volcanism in the past several million years and present new geochronologic results from major ignimbrite sheets exposed in Kamchatka. These ignimbrites are found in the vicinity of morphologically-preserved rims of partially eroded source calderas with diameters from ∼
2 to ∼
30
km and with estimated volumes of eruptions ranging from 10 to several hundred cubic kilometers of magma. We also identify and date two of the largest ignimbrites: Golygin Ignimbrite in southern Kamchatka (0.45
Ma), and Karymshina River Ignimbrites (1.78
Ma) in south-central Kamchatka. We present whole-rock geochemical analyses that can be used to correlate ignimbrites laterally. These large-volume ignimbrites sample a significant proportion of remelted Kamchatkan crust as constrained by the oxygen isotopes. Oxygen isotope analyses of minerals and matrix span a 3‰ range with a significant proportion of moderately low-
δ
18O values. This suggests that the source for these ignimbrites involved a hydrothermally-altered shallow crust, while participation of the Cretaceous siliceous basement is also evidenced by moderately elevated
δ
18O and Sr isotopes and xenocryst contamination in two volcanoes. The majority of dates obtained for caldera-forming eruptions coincide with glacial stages in accordance with the sediment record in the NW Pacific, suggesting an increase in explosive volcanic activity since the onset of the last glaciation 2.6
Ma. Rapid changes in ice volume during glacial times and the resulting fluctuation of glacial loading/unloading could have caused volatile saturation in shallow magma chambers and, in combination with availability of low-
δ
18O glacial meltwaters, increased the proportion of explosive vs effusive eruptions. The presented results provide new constraints on Pliocene–Pleistocene volcanic activity in Kamchatka, and thus constrain an important component of the Pacific Ring of Fire.
The E2 protein in classical swine fever (CSF) virus (CSFV) is the major virus structural glycoprotein and is an essential component of the viral particle. E2 has been shown to be involved in several ...functions, including virus adsorption, induction of protective immunity, and virulence in swine. Using the yeast two-hybrid system, we previously identified a swine host protein, dynactin subunit 6 (DCTN6) (a component of the cell dynactin complex), as a specific binding partner for E2. We confirmed the interaction between DCTN6 and E2 proteins in CSFV-infected swine cells by using two additional independent methodologies, i.e., coimmunoprecipitation and proximity ligation assays. E2 residues critical for mediating the protein-protein interaction with DCTN6 were mapped by a reverse yeast two-hybrid approach using a randomly mutated E2 library. A recombinant CSFV mutant, E2ΔDCTN6v, harboring specific substitutions in those critical residues was developed to assess the importance of the E2-DCTN6 protein-protein interaction for virus replication and virulence in swine. CSFV E2ΔDCTN6v showed reduced replication, compared with the parental virus, in an established swine cell line (SK6) and in primary swine macrophage cultures. Remarkably, animals infected with CSFV E2ΔDCTN6v remained clinically normal during the 21-day observation period, which suggests that the ability of CSFV E2 to bind host DCTN6 protein efficiently during infection may play a role in viral virulence.
Structural glycoprotein E2 is an important component of CSFV due to its involvement in many virus activities, particularly virus-host interactions. Here, we present the description and characterization of the protein-protein interaction between E2 and the swine host protein DCTN6 during virus infection. The E2 amino acid residues mediating the interaction with DCTN6 were also identified. A recombinant CSFV harboring mutations disrupting the E2-DCTN6 interaction was created. The effect of disrupting the E2-DCTN6 protein-protein interaction was studied using reverse genetics. It was shown that the same amino acid substitutions that abrogated the E2-DCTN6 interaction
constituted a critical factor in viral virulence in the natural host, domestic swine. This highlights the potential importance of the E2-DCTN6 protein-protein interaction in CSFV virulence and provides possible mechanisms of virus attenuation for the development of improved CSF vaccines.
Although the substorm current wedge (SCW) is recognized as a basic 3‐D current system of the substorm expansion phase, its existing models still do not extend beyond a cartoon‐like sketch, and very ...little is known of how well they reproduce magnetic variations observed in the magnetosphere during substorms. A lack of a realistic quantitative SCW model hampers testing model predictions against large sets of spacecraft data. This paper (1) presents a computationally efficient and flexible model with a realistic geometry of field‐aligned currents, conveniently parameterized by the SCW strength, longitudinal width, and position, all derived from ground‐based midlatitude magnetic variations; and (2) tests the model against INTERMAGNET network observations during substorms and compares its predictions with space magnetometer data. The testing demonstrated significant and systematic discrepancies between the observed and predicted magnetic variations, depending on spacecraft location, concurrent magnetotail configuration, and substorm phase. In particular, we found that the net SCW current derived from the midlatitude field variations corresponds to only a relatively small and variable fraction of the distant 3‐D substorm current, inferred from spacecraft data in the lobe and at geosynchronous distance. The discrepancy can be partly attributed to additional region 2 polarity field‐aligned currents in the same longitudinal sector, associated with azimuthal diversion of the earthward plasma flow when it encounters the region of strong quasi‐dipolar field in the inner magnetosphere.
Key Points
Quantitative model of substorm current wedge
Testing model against observations in the lobes, at GEO orbit and on the ground
General agreement but also systematic diferences between modeled and real field
Substorm current wedge (SCW) formation is associated with global magnetic field reconfiguration during substorm expansion. We combine a two-loop model SCW (SCW2L) with a background magnetic field ...model to investigate distortion of the ionospheric footpoint pattern in response to changes of different SCW2L parameters. The SCW-related plasma sheet footprint shift results in formation of a pattern resembling an auroral bulge, the poleward expansion of which is controlled primarily by the total current in the region 1 sense current loop (I1). The magnitude of the footprint latitudinal shift may reach ∼ 10° corrected geomagnetic latitude (CGLat) during strong substorms (I1= 2 MA). A strong helical magnetic field around the field-aligned current generates a surge-like region with embedded spiral structures, associated with a westward traveling surge (WTS) at the western end of the SCW. The helical field may also contribute to rotation of the ionospheric projection of narrow plasma streams (auroral streamers). Other parameters, including the total current in the second (region 2 sense) loop, were found to be of secondary importance. Analyzing two consecutive dipolarizations on 17 March 2010, we used magnetic variation data obtained from a dense midlatitude ground network and several magnetospheric spacecraft, as well as the adaptive AM03 model, to specify SCW2L parameters, which allowed us to predict the magnitude of poleward auroral expansion. Auroral observations made during the two substorm activations demonstrate that the SCW2L combined with the AM03 model nicely describes the azimuthal progression and the observed magnitude of the auroral expansion. This finding indicates that the SCW-related distortions are responsible for much of the observed global development of bright auroras.
The endogenous cannabinoid 2-arachidonoyl glycerol (2-AG) is an anti-fibrotic lipid mediator that induces apoptosis in hepatic stellate cells (HSCs), but not in hepatocytes. However, the exact ...molecular mechanisms of this selective induction of HSC death are still unresolved. Interestingly, the inducible isoform of cyclooxygenase, COX-2, can metabolize 2-AG to pro-apoptotic prostaglandin glycerol esters (PG-GEs). We analyzed the roles of COX-2 and endocannabinoid-derived PG-GEs in the differential susceptibility of primary activated HSCs and hepatocytes toward 2-AG-induced cell death. HSCs displayed significant COX-2 expression in contrast to hepatocytes. Similar to 2-AG, treatment of HSCs with PGD2-GE dose-dependently induced cell death independently from cannabinoid receptors that was accompanied by PARP- and caspase 3-cleavage. In contrast to 2-AG, PGD2-GE failed to induce significant ROS formation in HSCs, and depletion of membrane cholesterol did not rescue HSCs from PGD2-GE-induced apoptosis. These findings indicate differential engagement of initial intracellular signaling pathways by 2-AG and its COX-2-derived metabolite PGD2-GE, but similar final cell death pathways. Other PG-GEs, such as PGE2-or PGF2α-GE did not induce apoptosis in HSCs. Primary rat hepatocytes were mainly resistant against 2-AG- and PGD2-GE-induced apoptosis. HSCs, but not hepatocytes were able to metabolize 2-AG to PGD2-GE. As a proof of principle, HSCs from COX-2−/− mice lacked PDG2-GE production after 2-AG treatment. Accordingly, COX-2−/− HSCs were resistant against 2-AG-induced apoptosis. In conclusion, the divergent expression of COX-2 in HSCs and hepatocytes contributes to the different susceptibility of these cell types towards 2-AG-induced cell death due to the generation of pro-apoptotic PGD2-GE by COX-2 in HSCs. Modulation of COX-2-driven metabolization of 2-AG may provide a novel physiological concept allowing the specific targeting of HSCs in liver fibrosis.
Display omitted Scheme of proposed 2-arachidonoyl glycerol (2-AG) death signaling in hepatic stellate cells (HSCs). 2-AG binds to unknown structures in cholesterol rich lipid rafts. Primarily, 2-AG leads to intramitochondrial reactive oxygen species (ROS) production. Secondly, 2-AG is also metabolized to prostaglandin D2 glycerol ester (PGD2-GE) in the cytoplasm by cyclooxygenase-2 (COX-2). PGD2-GE and mitochondrial ROS induced by 2-AG lead to cytochrome C release from mitochondria to cause caspase-3-dependent apoptotic cell death in HSCs.
•The endocannabinoid 2-AG selectively induces death in HSCs, but not in hepatocytes.•2-AG is hydrolyzed by COX-2 to PGD2-GE in HSCs, but not in hepatocytes.•PGD2-GE significantly contributes to selective 2-AG-induced HSC apoptosis.•2-AG metabolization by COX-2 in HSCs represents a novel anti-fibrotic concept.
Unprecedented spacecraft and instrumental coverage and the isolated nature and distinct step‐like development of a substorm on 17 March 2010 has allowed validation of the two‐loop substorm current ...wedge model (SCW2L). We find a close spatiotemporal relationship of the SCW with many other essential signatures of substorm activity in the magnetotail and demonstrate its azimuthally localized structure and stepwise expansion in the magnetotail. We confirm that ground SCW diagnostics makes it possible to reconstruct and organize the azimuthal spatiotemporal substorm development pattern with accuracy better than 1 h magnetic local time (MLT) in the case of medium‐scale substorm. The Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE)‐based study of global field‐aligned current distribution indicates that (a) the SCW‐related field‐aligned current system consists of simultaneously activated R1‐ and R2‐type currents, (b) their net currents have a R1‐sense, and (c) locations of net current peaks are consistent with the SCW edge locations inferred from midlatitude variations. Thanks to good azimuthal coverage of four GOES and three Time History of Events and Macroscale Interactions during Substorms spacecraft, we evaluated the intensities of the SCW R1‐ and R2‐like current loops (using the SCW2L model) obtained from combined magnetospheric and ground midlatitude magnetic observations and found the net currents consistent (within a factor of 2) with the AMPERE‐based estimate. We also ran an adaptive magnetospheric model and show that SCW2L model outperforms it in predicting the magnetic configuration changes during substorm dipolarizations.
Key Points
Azimuthal SCW dynamics nicely order various substorm signatures in the tail
AMPERE confirms quadrupolar FAC source of SCW supporting two‐loop model
SCW2L model outperforms other models in describing dipolarized configuration
The presence of skeletal metastases in patients suffering from cancer leads to a variety of clinical complications. Bisphosphonates are a class of drugs with a potent bone resorption inhibition ...activity that have found increasing utility in treating and managing patients with metastatic bone disease. Several clinical trials have demonstrated that bisphosphonates have clinical value in the treatment and management of skeletal metastases derived from advanced prostate cancer. Currently, the mechanism(s) through which bisphosphonates exert their activity is only beginning to be understood. We have studied the effects of bisphosphonate treatment on the growth of prostate cancer cell lines in vitro. Treatment of PC3, DU145, and LNCaP cells with pamidronate or zoledronate significantly reduced the growth of all three cell lines. Using flow cytometry, pamidronate treatment (100 microM) was shown to induce significant amounts of cell death in all three cell lines studied. In contrast, treatment with zoledronate (100 microM) did not induce cell death, instead exerting dramatic effects on cell proliferation, as evidenced by a major increase in cells present in the G0-G1 and S phase. Although both drugs reduced prostate cancer cell growth in the presence of serum, zoledronate was more potent under these conditions, disrupting growth at doses as low as 25 microM in the presence of 5% fetal bovine serum. These results raise the intriguing possibility that the observed clinical utility of bisphosphonates in managing skeletal metastases may in part derive from direct inhibition of prostate cancer cell growth in the bone microenvironment.
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