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Resection of brain tumors frequently causes injury to the surrounding brain tissue that exacerbates cerebral edema by activating an inflammatory cascade. Although corticosteroids are often utilized peri-operatively to alleviate the symptoms associated with brain edema, they increase operative morbidities and suppress the efficacy of immunotherapy. Thus, novel approaches to minimize cerebral edema caused by neurosurgical procedures will have significant utility in the management of patients with brain tumors. We have studied the role of the receptor for advanced glycation end products (RAGE) and its ligands on inflammatory responses to neurosurgical injury in mice and humans. Blood–brain barrier (BBB) integrity and neuroinflammation were characterized by Nanostring, flow cytometry, qPCR, and immunoblotting of WT and RAGE knockout mice brains subjected to surgical brain injury (SBI). Human tumor tissue and fluid collected from the resection cavity of patients undergoing craniotomy were also analyzed by single-cell RNA sequencing and ELISA. Genetic ablation of RAGE significantly abrogated neuroinflammation and BBB disruption in the murine SBI model. The inflammatory responses to SBI were associated with infiltration of S100A9-expressing myeloid-derived cells into the brain. Local release of pro-inflammatory S100A9 was confirmed in patients following tumor resection. RAGE and S100A9 inhibitors were as effective as dexamethasone in attenuating neuroinflammation. However, unlike dexamethasone and S100A9 inhibitor, RAGE inhibition did not diminish the efficacy of anti-PD-1 immunotherapy in glioma-bearing mice. These observations confirm the role of the RAGE axis in surgically induced neuroinflammation and provide an alternative therapeutic option to dexamethasone in managing post-operative cerebral edema. [ABSTRACT FROM AUTHOR]

Abstract Interferon-tau (IFNT) is the main signal for the maternal recognition of pregnancy in ruminants, and exerts its effects by stimulating the expression of interferon-stimulated genes, including the expression of interferon-stimulated gene15 kDa protein (ISG15). Progesterone (P4) exerts significant immune effects on the uterus during early pregnancy in ruminants that are partly mediated by progesterone-induced blocking factor (PIBF). The thymus is necessary for the normal development of immunologic function. In this study, thymuses were obtained on day 16 of the estrous cycle and on days 13, 16 and 25 of pregnancy (n = 6 for each group) from ewes. Our results showed that the expression of ISG15, P4 receptor (PGR) and PIBF mRNA and the expression of ISG15 and ISG15-conjugated proteins were upregulated in the thymuses during early pregnancy, and the 89-kDa PGR isoform and the 80-kDa PIBF variant were expressed constantly in the thymuses. However, there was no expression of the 60-kDa PGR isoform and the 62-kDa PIBF variant on day 16 of the estrous cycle. ISG15 and ISG15-conjugated proteins were limited to the epithelial reticular cells, capillaries and thymic corpuscles. This paper reports for the first time that early pregnancy exerts its effects on the thymus through IFNT and P4 in sheep. Highlights • Upregulation expression of ISG15 mRNA and protein in the thymus during early pregnancy in sheep. • Upregulation expression of PGR mRNA and protein in the thymus during early pregnancy in sheep. • Upregulation expression of PIBF mRNA and protein in the thymus during early pregnancy in sheep. • ISG15 protein was limited to the epithelial reticular cells, capillaries and thymic corpuscles in the thymus. [ABSTRACT FROM AUTHOR]

China is the largest CO 2 emitting country on Earth. During the COVID-19 pandemic, China implemented strict government control measures on both outdoor activity and industrial production. These control measures, therefore, were expected to significantly reduce anthropogenic CO 2 emissions. However, large discrepancies still exist in the estimated anthropogenic CO 2 emission reduction rate caused by COVID-19 restrictions, with values ranging from 10% to 40% among different approaches. Here, we selected Nanchang city, located in eastern China, to examine the impact of COVID-19 on CO 2 emissions. Continuous atmospheric CO 2 and ground-level CO observations from January 1st to April 30th, 2019 to 2021 were used with the WRF-STILT atmospheric transport model and a priori emissions. And a multiplicative scaling factor and Bayesian inversion method were applied to constrain anthropogenic CO 2 emissions before, during, and after the COVID-19 pandemic. We found a 37.1–40.2% emission reduction when compared to the COVID-19 pandemic in 2020 with the same period in 2019. Carbon dioxide emissions from the power industry and manufacturing industry decreased by 54.5% and 18.9% during the pandemic period. The power industry accounted for 73.9% of total CO 2 reductions during COVID-19. Further, emissions in 2021 were 14.3–14.9% larger than in 2019, indicating that economic activity quickly recovered to pre-pandemic conditions. [Display omitted] • A 40% decrease of anthropogenic CO 2 emissions was observed during the 2020 COVID-19 pandemic. • Power industry accounted for 73.9% of total CO 2 reductions during COVID-19. • Anthropogenic CO 2 emissions in 2021 were 14% larger than in 2019. • The recovery of CO 2 emissions between year 2021 and 2019 indicates a fast economic rebound. • Point source location mismatches should be evaluated in city scale emission inversion. [ABSTRACT FROM AUTHOR]

Abstract: The goal of this study was to evaluate the mechanism of cyclodextrin-based nanoparticle (CDP-NP) uptake into a murine glioma model. Using mixed in vitro culture systems, we demonstrated that CDP-NPs were preferentially taken up by BV2 and N9 microglia (MG) cells compared with GL261 glioma cells. Fluorescent microscopy and flow cytometry analysis of intracranial GL261 gliomas confirmed these findings and demonstrated a predominant CDP-NP uptake by macrophages (MPs) and MG within and around the tumor site. Notably, in mice bearing bilateral intracranial tumor, MG and MPs carrying CDP-NPs were able to migrate to the contralateral tumors. In conclusion, these studies better characterize the cellular distribution of CDP-NPs in intracranial tumors and demonstrate that MPs and MG could potentially be used as nanoparticle drug carriers into malignant brain tumors. From the Clinical Editor: The goal of this study was to evaluate the mechanism of cyclodextrin-based nanoparticle (CDP-NP) uptake into a murine glioma model. CDP-NP was preferentially taken up microglia (MG) cells as compared to glioma cells. A predominant CDP-NP uptake by macrophages and MG was also shown in and around the tumor site. Macrophages and MG could potentially be used as nanoparticle drug carriers into malignant brain tumors. [Copyright &y& Elsevier]

Abstract S100B, a member of the multigene family of Ca2+-binding proteins, is overexpressed by most malignant gliomas but its biological role in gliomagenesis is unclear. Recently, we demonstrated that low concentrations of S100B attenuated microglia activation through the induction of STAT3. Furthermore, S100B downregulation in a murine glioma model inhibited macrophage trafficking and tumor growth. Based on these observations, we hypothesized that S100B inhibitors may have antiglioma properties through modulation of tumor microenvironment. To discover novel S100B inhibitors, we developed a high-throughput screening cell-based S100B promoter-driven luciferase reporter assay. Initial screening of 768 compounds in the NIH library identified 36 hits with >85% S100B inhibitory activity. Duloxetine (Dul, an SNRI) was selected for the initial proof-of-concept studies. At low concentrations (1–5 μM) Dul inhibited S100B and CCL2 production in mouse GL261 glioma cells, but had minimal cytotoxic activity in vitro. In vivo , however, Dul (30 mg/kg/14 days) inhibited S100B production, altered the polarization and trafficking of tumor-associated myeloid-derived cells, and inhibited the growth of intracranial GL261 gliomas. Dul therapeutic efficacy, however, was not observed in the K-Luc glioma model that expresses low levels of S100B. These findings affirm the role of S100B in gliomagenesis and justify the development of more potent S100B inhibitors for glioma therapy. Graphical abstract Image 1 Highlights • S100B is overexpressed by most malignant gliomas but its biological role in gliomagenesis is unclear. • S100B downregulation in a murine glioma model inhibits macrophage trafficking and tumor growth. • High-throughput screening assay was developed to discover novel S100B inhibitors. • Duloxetine, a serotonin-norepinephrine reuptake inhibitor, was identified as an inhibitor of S100B. • In a murine glioma model, duloxetine inhibited S100B production and tumor growth, and altered polarization of macrophages. [ABSTRACT FROM AUTHOR]

The most of embryo losses occur before the day 16 after artificial insemination, but there is no low cost and easy operation that can detect pregnancy with high accuracy within three weeks post-insemination in cattle. In this study, blood samples were collected at day 18 of the estrous cycle, and days 18, 25 and 35 of pregnancy, and relative levels of interferon stimulated genes (ISGs), Toll-like receptor (TLRs), complement components, early pregnancy factor (EPF) and pregnancy-associated plasma protein A (PAPPA) proteins were analyzed through Western blot. In addition, a colloidal gold immunochromatographic test strip was developed using the selected antibody, and the test was used for early pregnancy diagnosis. The results showed that there were changes in relative levels of plasma ISGs, TLRs, complement components, EPF and PAPPA proteins during early pregnancy in cattle, and complement component 1q (C1q) could be used as an ideal marker to develop a colloidal gold immunochromatographic test strip for early pregnancy diagnosis. In addition, the accuracy of pregnancy diagnosis by this test strip was 91.67% (11/12) for pregnant cows and 80% (8/10) nonpregnant cows at day 18 after insemination. In conclusion, the changes in plasma ISGs, TLRs, complement components, EPF and PAPPA proteins may be related to the maternal systemic immune modulation during early pregnancy, and a colloidal gold immunochromatographic test strip was developed for early pregnancy diagnosis using C1q as the ideal marker in cows. However, this colloidal gold immunochromatographic test strip needs further studies to improve the accuracy. • Early pregnancy induces changes in plasma ISGs, TLRs, complement components. • C1q can be used as an ideal marker for early pregnancy diagnosis in cows. • Development of an immunochromatographic test strip for early pregnancy diagnosis. [ABSTRACT FROM AUTHOR]

Thymus is a primary lymphoid organ, must adapt to the presence of fetal alloantigens. Prostaglandins (PGs) have diverse effects to activate or inhibit the immune response, but effects of early pregnancy on the expression of PG synthases in ovine maternal thymus are unclear. In this study, ovine thymic samples were obtained at day 16 of the estrous cycle, and days 13, 16 and 25 of pregnancy. The expression of PG synthases, including cyclooxygenase 1 (COX-1), COX-2, PGE2 synthase (PTGES), and a prostaglandin F2α synthase (Aldo-keto reductase family 1, member B1, AKR1B1), was evaluated using quantitative real-time PCR, Western blot and immunohistochemistry analysis. In addition, the thymus/body ratio was also calculated. Our results showed that the expression of COX-2 mRNA and protein, AKR1B1 mRNA and dimer were up-regulated on day 25 of pregnancy (P < 0.05), and expression of COX-1, PTGES mRNA and protein, AKR1B1 monomer and thymus/body ratio were similar at different stages of pregnancy and the estrous cycle. The immunohistochemistry results showed that the COX-2 and AKR1B1 proteins were located in the stromal cells, capillaries and thymic corpuscles. This is the first study to report that expression of COX-2 and AKR1B1 dimer is up-regulated in the maternal thymus during early pregnancy, suggesting that early pregnancy exerts its effects on maternal thymus, which is involved in immunomodulation during early pregnancy in sheep. • Up-regulation expression of COX-2 mRNA and protein in the thymus on day 25 of pregnancy. • Up-regulation expression of AKR1B1 mRNA and dimer in the thymus on day 25 of pregnancy. • COX-2 and AKR1B1 proteins were limited to the stromal cells, capillaries and thymic corpuscles in the thymus. [ABSTRACT FROM AUTHOR]

Abstract As a fetal allograft to the mother, early conceptus regulates the intrauterine immune and systemic immune responses during early pregnancy in sheep. However, expression of T helper 1 (Th1) and Th2 cytokines in maternal lymph nodes is unclear during early pregnancy in sheep. In this study, inguinal lymph nodes were obtained on day 16 of the estrous cycle and on days 13, 16 and 25 of pregnancy (n = 4 for each group) in ewes, and qRT-PCR, western blot and immunohistochemistry were used to compare the expression of Th1 and Th2 cytokines in the lymph nodes. Our results showed that there were the highest levels of Th1 cytokines (IFN-γ, TNF-β and IL-2) and Th2 cytokines (IL-4, IL-5, IL-6 and IL-10) in the lymph nodes on day 13 or 16 of pregnancy. Furthermore, there were a downregulation of TNF-β and IL-2 and an upregulation of IL-5 and IL-10 on day 25 of pregnancy compared with that in nonpregnancy, with no significant difference in the expression of IFN-γ, IL-4, and IL-6 between the ewes on day 25 of pregnancy and nonpregnancy. The immunohistochemistry results showed that the IL-2 and IL-10 proteins were limited to the subcapsular sinus and trabeculae in the cortex, lymph sinus. In conclusion, early pregnancy exerted its effects on the lymph node and induced a Th2-biased response, which was essential for a normal pregnancy in sheep. Highlights • Downregulation of tumor necrosis factor beta and IL-2 in the lymph node. • Upregulation of IL-5 and IL-10 in the lymph node. • IL-2 and IL-10 were localized in the subcapsular sinus and trabeculae in the cortex, medullary sinuses. [ABSTRACT FROM AUTHOR]

The spleen plays a key role in immune regulation. Progesterone (P4) exhibits different immunological effects through binding to different types of receptor. In the present study, splenic samples were obtained at day 16 of non-pregnancy and days 13, 16, and 25 of pregnancy to study the expression of P4 receptor (PGR) and P4-induced blocking factor (PIBF) in ewes through quantitative real-time PCR, Western blot and immunohistochemistry analysis. Our results showed that the relative expression levels of PGR and PIBF mRNA increased from day 13–16 in pregnant ewes, but decreased from day 16–25, and the 26 kDa isoform of PGR and the 22 kDa variant of PIBF were down-regulated in the spleens at day 25 of pregnancy compared with expression at day 16 of the oestrous cycle and days 13 and 16 of pregnancy. The immunohistochemistry test results confirmed that PGR and PIBF proteins were localized in the cytoplasm of cells in the capsule, trabeculae and splenic cords. This paper reports for the first time that the 26 kDa isoform of PGR and the 22 kDa variant of PIBF were down-regulated during early pregnancy, which may be essential for normal pregnancy in ewes. [ABSTRACT FROM AUTHOR]

Lymph nodes are the sites where the immune reaction or suppression takes place. Progesterone (P4) exerts an essential effect of the immunomodulation on the maternal uterus during early pregnancy in ruminants. At present study, the inguinal lymph nodes were obtained at day 16 of non-pregnancy, days 13, 16 and 25 of pregnancy (n = 3 for each group) in ewes, and RT-PCR assay, western blot and immunohistochemistry analysis were used to analyze to the effect of early pregnancy on the expression of P4 receptor (PGR) and progesterone-induced blocking factor (PIBF) in the lymph nodes. Our results showed that the PGR and PIBF mRNA were up-regulated in the lymph nodes in pregnant ewes, and the PGR isoform (60 kDa) and the PIBF variant (75 kDa) were expressed constantly in the lymph nodes. However, there was no expression of the PGR isoform (40 kDa) and the PIBF variant (48 kDa) at day 16 of the estrous cycle. The immunohistochemistry results confirmed that the PGR and PIBF proteins were limited to the subcapsular sinus and trabeculae in the cortex, medullary sinuses, and were localized in the cytoplasm of the specific cells. This paper reports for the first time that early pregnancy exerts its effect on the specific cells in the lymph nodes through P4, which results in the up-regulated expression of the PGR mRNA and 40 kDa isoform, the PIBF mRNA and 48 kDa variant, and is involved in the immunoregulation of the lymph nodes through a cytosolic pathway in ewes. [ABSTRACT FROM AUTHOR]