Background and Aims
Liver ischemia/reperfusion injury (IRI) induces local and systemic inflammation in which neutrophil extracellular traps (NETs) are major drivers. IRI markedly augments metastatic ...growth, which is consistent with the notion that the liver IRI can serve as a premetastatic niche. Exercise training (ExT) confers a sustainable protection, reducing IRI in some animal models, and has been associated with improved survival in patients with cancer; however, the impact of ExT on liver IRI or development of hepatic metastases is unknown.
Approach and Results
Mice were randomized into exercise (ExT) and sedentary groups before liver IRI and tumor injection. Computerized dynamic network analysis of 20 inflammatory mediators was used to dissect the sequence of mediator interactions after ischemia/reperfusion (I/R) that induce injury. ExT mice showed a significant decrease in hepatic IRI and tissue necrosis. This coincided with disassembly of complex networks among inflammatory mediators seen in sedentary mice. Neutrophil infiltration and NET formation were decreased in the ExT group, which suppressed the expression of liver endothelial cell adhesion molecules. Concurrently, ExT mice revealed a distinct population of infiltrating macrophages expressing M2 phenotypic genes. In a metastatic model, fewer metastases were present 3 weeks after I/R in the ExT mice, a finding that correlated with a marked increase in tumor‐suppressing T cells within the tumor microenvironment.
Conclusions
ExT preconditioning mitigates the inflammatory response to liver IRI, protecting the liver from injury and metastases. In light of these findings, potential may exist for the reduction of liver premetastatic niches induced by liver IRI through the use of ExT as a nonpharmacologic therapy before curative surgical approaches.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Conventional breast MRI is highly sensitive for cancer detection but prompts some false positives. We performed a prospective, multicenter study to determine whether apparent diffusion coefficients ...(ADCs) from diffusion-weighted imaging (DWI) can decrease MRI false positives.
A total of 107 women with MRI-detected BI-RADS 3, 4, or 5 lesions were enrolled from March 2014 to April 2015. ADCs were measured both centrally and at participating sites. ROC analysis was employed to assess diagnostic performance of centrally measured ADCs and identify optimal ADC thresholds to reduce unnecessary biopsies. Lesion reference standard was based on either definitive biopsy result or at least 337 days of follow-up after the initial MRI procedure.
Of 107 women enrolled, 67 patients (median age 49, range 24-75 years) with 81 lesions with confirmed reference standard (28 malignant, 53 benign) and evaluable DWI were analyzed. Sixty-seven of 81 lesions were BI-RADS 4 (
= 63) or 5 (
= 4) and recommended for biopsy. Malignancies exhibited lower mean in centrally measured ADCs (mm
/s) than benign lesions 1.21 × 10
vs.1.47 × 10
;
< 0.0001; area under ROC curve = 0.75; 95% confidence interval (CI) 0.65-0.84. In centralized analysis, application of an ADC threshold (1.53 × 10
mm
/s) lowered the biopsy rate by 20.9% (14/67; 95% CI, 11.2%-31.2%) without affecting sensitivity. Application of a more conservative threshold (1.68 × 10
mm
/s) to site-measured ADCs reduced the biopsy rate by 26.2% (16/61) but missed three cancers.
DWI can reclassify a substantial fraction of suspicious breast MRI findings as benign and thereby decrease unnecessary biopsies. ADC thresholds identified in this trial should be validated in future phase III studies.
The auroral streamer is a type of auroral form commonly observed during geomagnetic substorms. Previous studies suggested a coupling between auroral streamers and channels of bursty bulk flows in the ...plasma sheet. However, whether one flow channel can map to multiple streamers is unclear. Here, we present an event containing consecutive auroral streamer subevents. The event features similar spatial and temporal development of auroral streamers in conjugate hemispheres. In most of the subevents, we observed that what an in‐space auroral camera saw as one streamer actually consisted of multiple streamers (i.e., a streamer bundle). A coordinated analysis of near‐earth injections and ionospheric currents suggests that one overall flow channel (or bubble) can map to a streamer bundle. Multiple streamer bundles and thus multiple overall flow channels can occur simultaneously at different local times. Evidence supports that the overall flow channel may consist of or split into several narrower flow channels and each maps to a streamer and causes a particle injection.
Plain Language Summary
Geomagnetic substorm is a complex energy release process involving many observable features in the geospace. Common substorm features include enhanced auroral activities and currents in the ionosphere, enhanced fluxes of energetic electrons and ions (injections), and localized bursty bulk flows (BBFs) in the nightside magnetosphere. It is well established that injection, BBF, and a type of aurora called auroral streamer are physically related. Here, we present an event when streamers form bundles in successive subevents and discuss how streamers and streamer bundles are related to BBF and injection. Auroral data show that these streamer bundles developed similarly in both hemispheres. We show observational evidence that a streamer bundle maps to an overall BBF and streamers within a bundle map to narrower BBFs.
Key Points
Similar spatial and temporal development of bundles of auroral streamers is observed in conjugate hemispheres
A streamer bundle may map to an overall bubble in the plasma sheet
Streamers within a streamer bundle may map to narrower bubbles
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In this paper, the anisotropic thermal conductivity characteristics of graphene wrinkles are observed for the first time using a non-equilibrium molecular dynamics method. Our results reveal that the ...wrinkling level has little effect on the thermal conductivity along the wrinkling direction. However, the wrinkling level plays an important role in the reduction of thermal conductivity along the texture direction, which results from the contributions of increased bond length, von Mises stress, broadening of phonon modes and G-band redshift. These results indicate that graphene wrinkles can be a promising candidate to modulate thermal conductivity properties in nanoscale thermal managements and thermoelectric devices.
Wrinkle-induced anisotropic thermal conductivity of graphene and its physical nature.
Changes in the genetic makeup of an organism can extend lifespan significantly if they promote tolerance to environmental insults and thus prevent the general deterioration of cellular function that ...is associated with aging. Here, we introduce the Jun N-terminal kinase (JNK) signaling pathway as a genetic determinant of aging in Drosophila melanogaster. Based on expression profiling experiments, we demonstrate that JNK functions at the center of a signal transduction network that coordinates the induction of protective genes in response to oxidative challenge. JNK signaling activity thus alleviates the toxic effects of reactive oxygen species (ROS). In addition, we show that flies with mutations that augment JNK signaling accumulate less oxidative damage and live dramatically longer than wild-type flies. Our work thus identifies the evolutionarily conserved JNK signaling pathway as a major genetic factor in the control of longevity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Meroterpenoids are natural products produced from polyketide and terpenoid precursors. A gene targeting system for A. terreus NIH2624 was developed, and a gene cluster for terretonin biosynthesis was ...characterized. The intermediates and shunt products were isolated from the mutant strains, and a pathway for terretonin biosynthesis is proposed. Analysis of two meroterpenoid pathways corresponding to terretonin in A. terreus and austinol in A. nidulans reveals that they are closely related evolutionarily.
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IJS, KILJ, NUK, PNG, UL, UM
In this paper, the conventional I- and T-type three-level neutral-point-clamped (3L-NPC) inverter for low-voltage renewable energy systems is first investigated. Literature research shows that the ...T-type inverter improves I-type's insulated-gate bipolar transistor (IGBT) + IGBT current paths. However, the IGBT + diode paths are the same. The calculation in this paper further reveals that the IGBT + diode current paths dominate the conduction losses and even the whole semiconductor losses. Based on the aforementioned recognitions, a novel T-type inverter is presented as an alternative to be applied in the low-voltage renewable energy systems. In the proposed 3L-NPC, four CoolMosfets replace the IGBT + diode middle bidirectional switch. In the proposed topology, there is no diode involved in the current path supposing the unity power factor. In this way, the conduction loss is expected to be reduced compared with that from the conventional T-type 3L-NPC, particularly in the low and medium power ranges.
Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors and has important roles in multiple aspects of cancer aggressiveness. Thus targeting STAT3 ...promises to be an attractive strategy for treatment of advanced metastatic tumors. Although many STAT3 inhibitors targeting the SH2 domain have been reported, few have moved into clinical trials. Targeting the DNA-binding domain (DBD) of STAT3, however, has been avoided due to its 'undruggable' nature and potentially limited selectivity. In a previous study, we reported an improved in silico approach targeting the DBD of STAT3 that resulted in a small-molecule STAT3 inhibitor (inS3-54). Further studies, however, showed that inS3-54 has off-target effect although it is selective to STAT3 over STAT1. In this study, we describe an extensive structure and activity-guided hit optimization and mechanistic characterization effort, which led to identification of an improved lead compound (inS3-54A18) with increased specificity and pharmacological properties. InS3-54A18 not only binds directly to the DBD and inhibits the DNA-binding activity of STAT3 both in vitro and in situ but also effectively inhibits the constitutive and interleukin-6-stimulated expression of STAT3 downstream target genes. InS3-54A18 is completely soluble in an oral formulation and effectively inhibits lung xenograft tumor growth and metastasis with little adverse effect on animals. Thus inS3-54A18 may serve as a potential candidate for further development as anticancer therapeutics targeting the DBD of human STAT3 and DBD of transcription factors may not be 'undruggable' as previously thought.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Summary
Background
Clearance of hepatitis B surface antigen (HBsAg) indicates clinical control of hepatitis B virus (HBV) infection. However, little is known about the impact of viral genomic ...variations on HBsAg loss.
Methods
We explored the association between viral genomic factors and HBsAg loss in 2121HBeAg‐negative patients. HBV pre‐core stop codon (1896) and basal core promoter (BCP) (1762/1764) sequences were determined in patients with HBV DNA ≥200 IU/mL (N = 1693). The effect of HBV genotype on HBsAg loss was further validated in the whole cohort of 3445 HBsAg carriers.
Results
The cumulative lifetime (age 28–75 years) incidence of HBsAg loss was 50.4% in 2121 HBeAg‐negative patients. We found that genotype C, but not pre‐core stop codon or BCP mutants, was associated with HBsAg loss. Compared to genotype B patients, genotype C patients had higher lifetime chance of HBsAg loss, with hazard ratio of 1.8 (95% confidence interval: 1.4–2.4). Multivariable analysis showed that male sex, elevated ALT levels, lower serum HBV DNA and HBsAg levels, and genotype C infection were associated with higher chance of HBsAg loss independently. We then performed sensitivity analysis, which re‐included HBeAg‐positive, cirrhotic and treatment‐experienced patients, and confirmed the robustness of our results in 3445 HBsAg carriers.
Conclusion
Genotype C infection, compared to genotype B, is associated with a higher lifetime chance of HBsAg loss in Asian HBV carriers.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
500.
Turbulent heating in a stratified medium Wang, C; Oh, S P; Ruszkowski, M
Monthly Notices of the Royal Astronomical Society,
01/2023, Volume:
519, Issue:
3
Journal Article
Peer reviewed
Open access
ABSTRACT
There is considerable evidence for widespread subsonic turbulence in galaxy clusters, most notably from Hitomi. Turbulence is often invoked to offset radiative losses in cluster cores, both ...by direct dissipation and by enabling turbulent heat diffusion. However, in a stratified medium, buoyancy forces oppose radial motions, making turbulence anisotropic. This can be quantified via the Froude number Fr, which decreases inward in clusters as stratification increases. We exploit analogies with MHD turbulence to show that wave–turbulence interactions increase cascade times and reduce dissipation rates ϵ ∝ Fr. Equivalently, for a given energy injection/dissipation rate ϵ, turbulent velocities u must be higher compared to Kolmogorov scalings. High-resolution hydrodynamic simulations show excellent agreement with the ϵ ∝ Fr scaling, which sets in for Fr ≲ 0.1. We also compare previously predicted scalings for the turbulent diffusion coefficient D ∝ Fr2 and find excellent agreement, for Fr ≲ 1. However, we find a different normalization, corresponding to stronger diffusive suppression by more than an order of magnitude. Our results imply that turbulent diffusion is more heavily suppressed by stratification, over a much wider radial range, than turbulent dissipation. Thus, the latter potentially dominates. Furthermore, this shift implies significantly higher turbulent velocities required to offset cooling, compared to previous models. These results are potentially relevant to turbulent metal diffusion in the galaxy groups and clusters (which is likewise suppressed), and to planetary atmospheres.
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