Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α.

Spatiotemporal regulation of tumor immunity remains largely unexplored. Here we identify a vascular niche that controls alternative macrophage activation in glioblastoma (GBM). We show that tumor-promoting macrophages are spatially proximate to GBM-associated endothelial cells (ECs), permissive for angiocrine-induced macrophage polarization. We identify ECs as one of the major sources for interleukin-6 (IL-6) expression in GBM microenvironment. Furthermore, we reveal that colony-stimulating factor-1 and angiocrine IL-6 induce robust arginase-1 expression and macrophage alternative activation, mediated through peroxisome proliferator-activated receptor-γ-dependent transcriptional activation of hypoxia-inducible factor-2α. Finally, utilizing a genetic murine GBM model, we show that EC-specific knockout of IL-6 inhibits macrophage alternative activation and improves survival in the GBM-bearing mice. These findings illustrate a vascular niche-dependent mechanism for alternative macrophage activation and cancer progression, and suggest that targeting endothelial IL-6 may offer a selective and efficient therapeutic strategy for GBM, and possibly other solid malignant tumors

A review on source identification of dissolved sulfate in groundwater: Advances, problems and development trends

Effective identification of the sources and biogeochemical processes of dissolved sulfate in groundwater is an important prerequisite for ensuring drinking water safety and aquatic ecological security and is of significance to manage and protect groundwater resources. In this review, the sources of groundwater sulfate and the typical range of δ34S and δ18O isotope from different sulfate sources are summarized by reviewing the literature; the identification of sulfate sources and S biogeochemical cycles by δ34S and δ18O isotope in sulfate is reviewed, and the existing problems and development trends are proposed. The source apportionment of groundwater sulfate sources has gone through the processes of hydrochemistry analysis→δ34S isotope→dual isotope→qualitative identification of multiple isotopes and tracers→quantitative evaluation. Due to the differences in sulfur and oxygen isotopes and the biogeochemical transformation processes in a specific region, there is still a larger uncertainty in the determination of groundwater sulfate sources.It is proposed to arrange the sampling points for collecting pollution sources and groundwater samples on the framework of groundwater flow systems and land use distributions and to analyze the hydrochemical components and the sulfur and oxygen isotope values of sulfate and other complementary tracer isotope values and/or concentrations in a specific area. The sources and their contributions of groundwater sulfate are analyzed using multidisciplinary and multi-methods based on the full integration of hydrogeochemistry, seepage field, land use and other information in a study area for the scientific implementation of groundwater resource protection and pollution prevention

Genetic Dissection of Quantitative Trait Loci for Hemostasis and Thrombosis on Mouse Chromosomes 11 and 5 Using Congenic and Subcongenic Strains

<div><p>Susceptibility to thrombosis varies in human populations as well as many inbred mouse strains. Only a small portion of this variation has been identified, suggesting that there are unknown modifier genes. The objective of this study was to narrow the quantitative trait locus (QTL) intervals previously identified for hemostasis and thrombosis on mouse distal chromosome 11 (<i>Hmtb6</i>) and on chromosome 5 (<i>Hmtb4</i> and <i>Hmtb5</i>). In a tail bleeding/rebleeding assay, a reporter assay for hemostasis and thrombosis, subcongenic strain (6A-2) had longer clot stability time than did C57BL/6J (B6) mice but a similar time to the B6-Chr11^A/J consomic mice, confirming the <i>Hmtb</i>6 phenotype. Six congenic and subcongenic strains were constructed for chromosome 5, and the congenic strain, 2A-1, containing the shortest A/J interval (16.6 cM, 26.6 Mbp) in the <i>Hmtb4</i> region, had prolonged clot stability time compared to B6 mice. In the 3A-2 and CSS-5 mice bleeding time was shorter than for B6, mice confirming the <i>Hmtb5</i> QTL. An increase in bleeding time was identified in another congenic strain (3A-1) with A/J interval (24.8 cM, 32.9 Mbp) in the proximal region of chromosome 5, confirming a QTL for bleeding previously mapped to that region and designated as <i>Hmtb10</i>. The subcongenic strain 4A-2 with the A/J fragment in the proximal region had a long occlusion time of the carotid artery after ferric chloride injury and reduced dilation after injury to the abdominal aorta compared to B6 mice, suggesting an additional locus in the proximal region, which was designated <i>Hmtb11</i> (5 cM, 21.4 Mbp). CSS-17 mice crossed with congenic strains, 3A-1 and 3A-2, modified tail bleeding. Using congenic and subcongenic analysis, candidate genes previously identified and novel genes were identified as modifiers of hemostasis and thrombosis in each of the loci <i>Hmtb</i>6, <i>Hmtb</i>4, <i>Hmtb</i>10, and <i>Hmtb</i>11. </p> </div

Tail Bleeding/Rebleeding Assay.

<p>A. First bleeding time. B. Clot Stability-time between first and second bleeding. Values are the mean ± SEM, n=7-28. One-way ANOVA, *P < 0.05, ** P < 0.01.</p

Comparison of Consomic and Congenic crosses.

<p>A. First bleeding time. B. Clot Stability-time between first and second bleeding. Values are the mean ± SEM, n=9-24, one-way ANOVA, * P< 0.05.</p

Genotype of Chromosome 11 Congenic and Subcongenic Mice.

<p>A. Marker positions. White bars-A/J, grey-uncertain, black-B6. B. First bleeding. C. Time between first and second bleeding. Values are the mean ± SEM, n=10-28, one-way ANOVA, * P< 0.05, **P<0.01.</p

Genotype of Chromosome 5 Congenics and Subcongenic Mice.

<p>Marker positions. White bars-A/J, grey-uncertain, black-B6, hatched-heterozygous.</p

EMILIN2 Regulates Platelet Activation, Thrombus Formation, and Clot Retraction

<div><p>Thrombosis, like other cardiovascular diseases, has a strong genetic component, with largely unknown determinants. EMILIN2, Elastin Microfibril Interface Located Protein2, was identified as a candidate gene for thrombosis in mouse and human quantitative trait loci studies. EMILIN2 is expressed during cardiovascular development, on cardiac stem cells, and in heart tissue in animal models of heart disease. In humans, the EMILIN2 gene is located on the short arm of Chromosome 18, and patients with partial and complete deletion of this chromosome region have cardiac malformations. To understand the basis for the thrombotic risk associated with EMILIN2, EMILIN2 deficient mice were generated. The findings of this study indicate that EMILIN2 influences platelet aggregation induced by adenosine diphosphate, collagen, and thrombin with both EMILIN2-deficient platelets and EMILIN2-deficient plasma contributing to the impaired aggregation response. Purified EMILIN2 added to platelets accelerated platelet aggregation and reduced clotting time when added to EMILIN2-deficient mouse and human plasma. Carotid occlusion time was 2-fold longer in mice with platelet-specific EMILIN2 deficiency, but stability of the clot was reduced in mice with both global EMILIN2 deficiency and with platelet-specific EMILIN2 deficiency. <i>In vitro</i> clot retraction was markedly decreased in EMILIN2 deficient mice, indicating that platelet outside-in signaling was dependent on EMILIN2. EMILIN1 deficient mice and EMILIN2:EMILIN1 double deficient mice had suppressed platelet aggregation and delayed clot retraction similar to EMILIN2 mice, but EMILIN2 and EMILIN1 had opposing affects on clot retraction, suggesting that EMILIN1 may attenuate the effects of EMILIN2 on platelet aggregation and thrombosis. In conclusion, these studies identify multiple influences of EMILIN2 in pathophysiology and suggest that its role as a prothrombotic risk factor may arise from its effects on platelet aggregation and platelet mediated clot retraction.</p></div

Ammonium enrichment, nitrate attenuation and nitrous oxide production along groundwater flow paths:Carbon isotopic and DOM optical evidence

Dissolved organic matter (DOM) plays a crucial role in the biogeochemical processing of reactive nitrogen in groundwater systems. However, the impacts of DOM on release of geogenic ammonium and transport and transformation of reactive nitrogen including nitrate attenuation under dynamics in groundwater level characteristic for floodplain environments remain unclear. In this study, we have identified the influence of riparian water level fluctuations on changes in the redox conditions, groundwater geochemical composition including the DOM mobilization in the piedmont recharge and the discharge area along groundwater flow paths. We have also evaluated the pivotal roles of DOM degradation in transport and transformation of nitrogen species including geogenic ammonium enrichment, nitrate attenuation, and dissolved nitrous oxide (N2O) production combining the stable carbon isotopic signatures and the optical characteristics of DOM. Along groundwater flow paths, the seasonal amplitudes of surface water levels were higher in the piedmont recharge area than those in the plain discharge area, and four DOM fluorescent components were identified through the parallel factor analysis (PARAFAC), with two terrestrial humic-like components (C1 and C2) in the piedmont recharge area, and two microbial humic-like components (C3 and C4) in the plain transition-discharge area. A positive correlation between stable dissolved inorganic carbon isotopic signatures (δ13C-DIC) and ammonium-nitrogen concentrations indicated that microbial degradation processes of DOM concomitantly promote the release of geogenic ammonium into groundwater. Ammonium enrichment and nitrate attenuation trend in groundwater was noted as one moved from the recharge area to the discharge area. Evidently, a clear correlation emerged where elevated dissolved N2O concentrations were linked to diminished ammonium-nitrogen levels and elevated nitrate-nitrogen levels. Additionally, groundwater exhibited higher dissolved N2O levels in the piedmont recharge area compared to the plain discharge area. These findings revealed that the impacts of groundwater DOM degradation on nitrate attenuation and dissolved N2O production in similar geogenic ammonium-affected Quaternary alluvial aquifers along groundwater flow paths, and established the theoretical basis for ensuring the security of local groundwater supply

Aggregation of platelets from E2^-/- and E2p^-/- mice.

<p>A,C. E2^-/- mice. B,D. E2p^-/- mice. A,B. Representative (3–5 experiments repeated 2–3 times with each platelet preparation) aggregometer tracing in PRP induced by 5μM ADP with platelets adjusted to 1.2x10⁸ per ml. C,D. Maximum amplitude from the platelet aggregometry tracings. The aggregation of PRP was induced with 1 μM or 5μM ADP added to PRP with platelets at adjusted to 0.8–1.2x10⁸ per mL pooled from 3 mice. Bars are mean±SEM, performed in triplicate. Statistical analysis, one-way ANOVA, Newman-Keuls post-test **P = 0.01, ***P = 0.001. E2^-/- (EMILIN2 deficient), E2p^-/- (EMILIN2 platelet deficient)</p