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Supplementary Figure S3

Supplementary Table from Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma

Multiple studies have associated the transcription factor IRF1 with tumor-suppressive activities. Here, we report an opposite tumor cell–intrinsic function of IRF1 in promoting tumor growth. IRF1-deficient tumor cells showed reduced tumor growth in MC38 and CT26 colon carcinoma and B16 melanoma mouse models. This reduction in tumor growth was dependent on host CD8+ T cells. Detailed profiling of tumor-infiltrating leukocytes did not show changes in the various T-cell and myeloid cell populations. However, CD8+ T cells that had infiltrated IRF1-deficieint tumors in vivo exhibited enhanced cytotoxicity. IRF1-deficient tumor cells lost the ability to upregulate PD-L1 expression in vitro and in vivo and were more susceptible to T-cell–mediated killing. Induced expression of PD-L1 in IRF1-deficient tumor cells restored tumor growth. These results indicate differential activity of IRF1 in tumor escape.

Supplementary Data from Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma

Supplementary Figure from Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma

Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) has a dismal prognosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study GBM's natural evolutionary trajectory by using rare multifocal samples. We sequenced 61,062 single cells from eight multifocal IDH wild-type primary GBMs and defined a natural evolution signature (NES) of the tumor. We show that the NES significantly associates with the activation of transcription factors that regulate brain development, including MYBL2 and FOSL2. Hypoxia is involved in inducing NES transition potentially via activation of the HIF1A–FOSL2 axis. High-NES tumor cells could recruit and polarize bone marrow–derived macrophages through activation of the FOSL2–ANXA1–FPR1/3 axis. These polarized macrophages can efficiently suppress T-cell activity and accelerate NES transition in tumor cells. Moreover, the polarized macrophages could upregulate CCL2 to induce tumor cell migration.Significance:GBM progression could be induced by hypoxia via the HIF1A–FOSL2 axis. Tumor-derived ANXA1 is associated with recruitment and polarization of bone marrow–derived macrophages to suppress the immunoenvironment. The polarized macrophages promote tumor cell NES transition and migration.This article is highlighted in the In This Issue feature, p. 2711

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Alcohol is a risk factor for pancreatic cancer. However, the molecular mechanism by which chronic alcohol consumption influences pancreatic cancer development is not well understood. We have recently demonstrated that chronic ethanol exposure of pancreatic normal ductal epithelial cells (HPNE) induces cellular transformation by generating cancer stem cells (CSCs). Here, we examined whether chronic ethanol treatment induces epithelial-mesenchymal transition in HPNE cells and promotes pancreatic cancer development in KC (Pdx1-Cre, and LSL-KrasG12D ) mice. Our data demonstrate that chronic ethanol exposure of HPNE cells induces SATB2 gene and those cells became highly motile. Ethanol treatment of HPNE cells results in downregulation of E-Cadherin and upregulation of N-Cadherin, Snail, Slug, Zeb1, Nanog and BMI-1. Suppression of SATB2 expression in ethanol-transformed HPNE cells inhibits EMT phenotypes. KC mice fed with an ethanol-containing diet show enhanced pancreatic cancer growth and development than those fed with a control diet. Pancreas isolated from KC mice fed with an ethanol-containing diet show higher expression of stem cell markers (CD133, CD44, CD24), pluripotency-maintaining factors (cMyc, KLF4, SOX-2, and Oct-4), N-Cadherin, EMT-transcription factors (Snail, Slug, and Zeb1), and lower expression of E-cadherin than those isolated from mice fed with a control diet. Furthermore, pancreas isolated from KC mice fed with an ethanol-containing diet show higher expression of inflammatory cytokines (TNF-α, IL-6, and IL-8) and PTGS-2 (COX-2) gene than those isolated from mice fed with a control diet. These data suggest that chronic alcohol consumption may contribute to pancreatic cancer development by generating inflammatory signals and CSCs.

A permineralized wood from the Deccan Intertrappean beds of central India is identified as a member of the family Lythraceae. The fossil wood found is similar to the modern genus Lagerstroemia and is characterized by diffuse porous to semi-ring porous wood, growth rings marked by marginal parenchyma, simple perforations, scanty paratracheal axial parenchyma, exclusively uniseriate homo to heterocellular rays and septate fibres with chambered crystals. This wood, Lagerstroemioxylon sp., is considerably older than the earlier known fossil records of this genus and confirms the presence of Lagerstroemia on the Indian subcontinent∼66 million years ago.

In nature, food availability stimulates hypothalamo-pituitary-gonadal (HPG) axis while its scarcity induces stress, which further stimulates hypothalamo-pituitary-adrenal (HPA) axis producing a detrimental effect on the avian reproductive physiology. The present experiment was designed to examine the interaction of stress like food restriction and estradiol on male reproductive physiology with special emphasis on estrogen receptor alpha (ERα) as these play crucial role in reproduction. To achieve this, 60 day old White Leghorn immature cockrels were taken and divided into four groups (n = 8 per group). One group was provided with food and water ad libitum. Second group was food restricted (FR) for 9 h/day after 5 days, third and fourth were administered with estradiol benzoate (EB 0.5 mg/100g/day) for 12 days. Fourth group was FR for 9 h/day after 5 days of EB treatment till last day of experiment (EB + FR). Immunofluorescent localization of ERα was principally in the pre-optic area and paraventricular nuclei of hypothalamus and in anterior pituitary gland. ERα expression was highly reduced (from 40 AU to 20 AU) after FR in testis but it increased (50 AU) after EB administration, EB + FR reflects a diminishing pattern in the increment after EB. FR decreased plasma estradiol while EB increased it. Increased plasma corticosterone, hydrogen peroxide, malondialdehyde, and decreased anti-oxidant enzymes in brain and testis of all groups indicate oxidative stress in the HPG axis. The increased ERα after EB and a decrease with FR and EB + FR support their reproductive function. Estrogen and its receptor alpha are responsible for maintaining epithelial morphology but FR along with EB administration modulates the testicular development by significantly decreasing its size (p

Due to the growing number of gadgets emitting electromagnetic radiation (EMR), particularly microwave (MW) radiation, in our daily lives, it is believed that EMR have both long-term and short-term biological impacts that are quite concerning for avian as well as human health. Due to the negative impact of MW emitting equipment on the biological system this study looks into the mechanistic approach by which low-level of 2.45 GHz MW radiation causes an oxidative stress and inflammatory response in the testes micro-environment which further gets regulated by estrogen receptor alpha (ERα) expression in immature Gallus gallus domesticus leading to male infertility. Two weeks old immature male chickens were exposed to non-thermal low-level 2.45-GHz MW radiation for 2 h/day for 30 days (power density = 0.1264 mw/cm

Baas, Pieter, Manchester, Steven, Wheeler, Elisabeth A., Srivastava, Rashmi (2022): Validation of the names linked to the oldest fossil Connaraceae wood (Connaroxylon, Connaroxylon dimorphum). Phytotaxa 558 (2): 249-250, DOI: 10.11646/phytotaxa.558.2.9, URL: http://dx.doi.org/10.11646/phytotaxa.558.2.9

Premise of research. Fossil fruits and seeds of Zingiberales provide essential data on the past diversity and distribution of the order, augmenting our understanding of the evolutionary history of ...

Smart drugs can change the way our mind functions. Smart drugs are also known as nootropics, which literally means the ability to bend or shape our mind. Smart drugs are classified into two main categories. They are classified based on their pharmacological action and their availability. The stimulant category of drugs is highly used and misused. There has been a rampant increase in the sale of smart drugs, which could be attributed to the rise in competition all over the world. Two major criteria for selecting a good drug are its mechanism of action and bioavailability. Owing to the short-term benefits of smart drugs, many countries have openly accepted this concept. There is still no concrete scientific evidence backing the safety and efficacy of these drugs. Some believe that this is just a fad that will soon pass, while others believe that this is something that will revolutionize our future.

Estrogen plays a key role in the regulation of reproductive behavior and control of the neuroendocrine system in both males and females. However, excessive quantity of exogenous estrogen produces a deleterious effect on the male reproductive system. To elucidate the mechanism by which estrogen modulates its receptor alpha (ESR1) in immature chicken during stress the study has been undertaken. The experiment investigated the physiological changes in the abundance of ESR1 in brain, pituitary and testes of immature male chickens after stress like water restriction. Twenty four immature male chickens were randomly assigned into four groups. The control group was provided with food and water ad libitum, second was water restricted 9 h each day for seven days (WR), third was treated with estradiol benzoate (EB) and fourth group was treated with EB followed by water restriction during last seven days of treatment (EB + WR). EB was administered at a dose of 0.5 mg/100 g/day for 12 days. EB administration as well as WR increases both the H2O2 and Malondialdehyde levels indicating oxidative stress in brain as well as in testis. Plasma corticosterone significantly increased in all groups while estradiol significantly decreased after water restriction. ESR1 protein was detected by immuno-fluorescence predominantly in the pre-optic area of the hypothalamus, pituitary and testes after EB administration. EB administration increases ESR1 proteins abundantly in the Sertoli cells, Leydig cells, spermatogonia and spermatids while WR decreases it. The decline in ESR1 proteins after EB administration during stress appears to be mediated by interaction of estrogen with hypothalamo-pituitary-adrenal (HPA) axis. Therefore, the findings substantiate the fact that WR and EB treatment increase the stress and alter the anti-oxidant enzymes via its receptor ESR1 in the brain, pituitary and testis of immature chicks. Moreover, these findings highlight the effect of estradiol in male chicks causing stress which is disrupting the normal physiological feedback mechanism in hormone release and the expression of receptor ESR1 along the hypothalamo-pituitary-gonadal (HPG) axis.

Food and water are closely associated with reproductive willingness in vertebrates. These are important for animals and their non-availability act as stressors which decrease sex steroid secretion suppressing reproductive behaviour. Oestrogen plays a crucial role in reproduction via its receptors alpha (ERα) and beta (ERβ). This study tested the hypothesis that ERα in testes of male Japanese quail is regulated during water and food deprivations. The present study reveals that both water and food deprivations cause oxidative stress and subsequently decrease catalase and superoxide dismutase activity, while these increase malondialdehyde and hydrogen peroxide. Both deprivations reduce plasma oestradiol whereas elevate corticosterone level. The immunofluorescent localization of ERα in the testes occurs predominantly in the seminiferous tubules of control while reduces after both food and water deprivations. All types of spermatogenic cells were seen in control testis, while after water and food deprivations size of seminiferous tubules and spermatogenic cells population decreased. Scanning electron microscopic study exhibited fully mature sperms in clusters with head and elongated flagellum, whereas after water deprivation maximum sperms were distorted, scattered with highly reduced head. On food deprivation, only few sperms were seen with head and tail. Thus, taking into account the localization of ERα in testis, it is obvious that oestrogens produced locally are involved in regulation of spermatogenesis and spermiogenesis during stress.

Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) has a dismal prognosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study GBM's natural evolutionary trajectory by using rare multifocal samples. We sequenced 61,062 single cells from eight multifocal IDH wild-type primary GBMs and defined a natural evolution signature (NES) of the tumor. We show that the NES significantly associates with the activation of transcription factors that regulate brain development, including MYBL2 and FOSL2. Hypoxia is involved in inducing NES transition potentially via activation of the HIF1A–FOSL2 axis. High-NES tumor cells could recruit and polarize bone marrow–derived macrophages through activation of the FOSL2–ANXA1–FPR1/3 axis. These polarized macrophages can efficiently suppress T-cell activity and accelerate NES transition in tumor cells. Moreover, the polarized macrophages could upregulate CCL2 to induce tumor cell migration. Significance: GBM progression could be induced by hypoxia via the HIF1A–FOSL2 axis. Tumor-derived ANXA1 is associated with recruitment and polarization of bone marrow–derived macrophages to suppress the immunoenvironment. The polarized macrophages promote tumor cell NES transition and migration. This article is highlighted in the In This Issue feature, p. 2711

Cinnamon has been used as a spice, condiment, and aromatic plant since centuries ago. Cinnamon is a small evergreen tree belonging to the genus Cinnamomum in the family Lauraceae. There are more than 250 species of cinnamon worldwide. In India, Cinnamomum verum and Cinnamomum cassia are the most common species grown in the Himalaya region. They have been used as folk medicine for the treatment of nausea, flatulent dyspepsia, coughs, diarrhea, malaria, gastric disorder, and to alleviate pain and inflammation in rheumatic arthritis. Therapeutic properties of cinnamon are due to the presence of bioactive constituents such as p-coumaric, cinnamaldehyde, cinnamic acid, and eugenol. Cinnamaldehyde and eugenol are the major active constituents responsible for its characteristic flavor, aroma, and therapeutic properties. Pharmacological studies found that it could be a promising candidate with potential for designing new drugs. This review is aimed to summarize the ethanomedicinal importance, phytochemistry, and wide spectrum of pharmacological and therapeutic applications of cinnamon.

Alcohol is a risk factor for pancreatic cancer. However, the molecular mechanism by which chronic alcohol consumption influences pancreatic cancer development is not well understood. We have recently demonstrated that chronic ethanol exposure of pancreatic normal ductal epithelial cells (HPNE) induces cellular transformation by generating cancer stem cells (CSCs). Here, we examined whether chronic ethanol treatment induces epithelial–mesenchymal transition in HPNE cells and promotes pancreatic cancer development in KC (Pdx1‐Cre, and LSL‐KrasG12D) mice. Our data demonstrate that chronic ethanol exposure of HPNE cells induces SATB2 gene and those cells became highly motile. Ethanol treatment of HPNE cells results in downregulation of E‐Cadherin and upregulation of N‐Cadherin, Snail, Slug, Zeb1, Nanog and BMI‐1. Suppression of SATB2 expression in ethanol‐transformed HPNE cells inhibits EMT phenotypes. KC mice fed with an ethanol‐containing diet show enhanced pancreatic cancer growth and development than those fed with a control diet. Pancreas isolated from KC mice fed with an ethanol‐containing diet show higher expression of stem cell markers (CD133, CD44, CD24), pluripotency‐maintaining factors (cMyc, KLF4, SOX‐2, and Oct‐4), N‐Cadherin, EMT‐transcription factors (Snail, Slug, and Zeb1), and lower expression of E‐cadherin than those isolated from mice fed with a control diet. Furthermore, pancreas isolated from KC mice fed with an ethanol‐containing diet show higher expression of inflammatory cytokines (TNF‐α, IL‐6, and IL‐8) and PTGS‐2 (COX‐2) gene than those isolated from mice fed with a control diet. These data suggest that chronic alcohol consumption may contribute to pancreatic cancer development by generating inflammatory signals and CSCs.

Glioblastoma (GBM), the most common and lethal brain tumor with a median survival rate of only 15 months, remains largely incurable despite intensive multimodal treatment, including immunotherapeutic strategies being tested in clinical trials. GBM is highly immunosuppressive and resistant to immunotherapy because glioma cells escape from effective antitumor immunity through programing the tumor microenvironment (TME). Owing to the tremendous heterogeneity and plasticity of tumor cells and the surrounding TME, understanding the mechanisms of immune evasion by GBM remains elusive. We have recently discovered that the Chitinase-3-like-1 (CHI3L1)-Galectin-3 (Gal3) protein binding complex can selectively promote tumor-associated macrophage migration and infiltration with a protumor M2-like phenotype and T cell-mediated immunosuppression, which are governed by a transcriptional program of NF-κB/CEBPβ in the CHI3L1/Gal3-PI3K/AKT/mTOR axis. The immunoprecipitation coupled to liquid chromatography-mass spectrometry analysis revealed that galectin 3–binding protein (Gal3BP) competes with Gal3 to bind with CHI3L1 for negative regulation of the CHI3L1-Gal3 mediated processes. Interestingly, a newly-developed Gal3BP mimetic peptide can disrupt CHI3L1-Gal3 interaction, resulting in decreasing migration of M2-like bone marrow-derived macrophages (BMDMs), increasing CD8+ T cell infiltration, reversing immunosuppression, and inhibiting tumor progression in vitro and in vivo. Analyzing PD-1 signaling activation, we found that the Gal3BP mimetic peptide significantly decreased PD-L1 expression in tumor cells. Correlation analysis showed that CHI31L and Gal3 (encoded by LGALS3 gene) are significantly associated with both PD-L1 and PD-L2 in GBM patient samples. Furthermore, overexpression of CHI3L1 increased expression levels of PD-L1 and PD-L2, and CHI3L1 deletion decreased their expression in GBM patient-derived neurosphere lines. The treatment with recombinant CHI3L1 protein significantly increased PD-L1 and PD-L2 expression in M2-like BMDMs (with high levels of endogenous Gal3). Collectively, these data suggest that CHI3L1 protein complexes control the GBM immunosuppressive microenvironment by PD-1/PD-L1/PD-L2 signaling, providing new immunotherapeutic strategies for this brain cancer.

PURPOSE: Coronavirus disease-2019 (COVID-19) may predispose to venous thromboembolism (VTE) and arterial thromboembolism because of excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. The understanding of the association might be helpful in early vigilant monitoring and better management of COVID-19 patients at high risk. Thus, in this meta-analysis, we aim to assess the association of VTE with the severity of COVID-19 disease.\ud \ud METHODS: A literature search was conducted on PubMed and Cochrane Central Register of Controlled Trials using the keywords "COVID-19 and thromboembolism" and "COVID-19 and embolism," till 20 February 2021. Thirteen studies including 6648 COVID-19 patients were incorporated in this systematic review and exploratory meta-analysis. \ud \ud RESULTS: The analysis revealed nearly three times more risk than intensive care unit (ICU) care in patients with VTE compared to non-VTE patients (RR: 2.78; 95% CI: 1.75-4.39; P

In nature, food availability stimulates hypothalamo-pituitary-gonadal (HPG) axis while its scarcity induces stress, which further stimulates hypothalamo-pituitary-adrenal (HPA) axis producing a detrimental effect on the avian reproductive physiology. The present experiment was designed to examine the interaction of stress like food restriction and estradiol on male reproductive physiology with special emphasis on estrogen receptor alpha (ERα) as these play crucial role in reproduction. To achieve this, 60 day old White Leghorn immature cockrels were taken and divided into four groups (

Animals are frequently exposed to various kinds of environmental stressors and estrogen is known to play important role in stress response besides its crucial role in regulation of cellular proliferation, metabolic activity and reproduction. The study investigates the estrogen antagonist, tamoxifen (TM), mediated estrogen receptor alpha (ERα) expression, to modulate stress induced parameters in chickens. The study further explores the activity of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPX) and malonaldehyde (MDA) in brain, ovary and shell gland during water deprivation (WD) and tamoxifen administration in sexually mature chicken. WD and TM administration both decrease the plasma estradiol while WD increases corticosterone. WD also elevates MDA concentration in the brain, ovary and shell gland while TM lowers it. WD and TM administration lowers the specific activity of SOD in brain and shell gland. In contrast, WD increases the specific activity of catalase, GPx and GR in the brain and shell gland, while TM decreases it. It appears that endogenous estradiol plays a crucial role in expression of antioxidant enzymes and tamoxifen acts as an antioxidant by reducing the oxidative stress in chicken. Abundant expression of ERα has been observed in the shell gland of egg laying birds while stress like water deprivation and TM down-regulates its expression. Thus, it can be concluded that expression of ERα in shell gland plays a predominant role in mediating estrogen action in response to water deprivation stress and tamoxifen.

The characteristics of obliquely propagating dust acoustic solitary wave in magnetized dusty plasma are analysed by considering the plasma to have electrons, two-temperature ions and massive dust grains with heavy charge. The reductive perturbation technique is used to derive relevant Korteweg-deVries (KdV) equation. The effect of density and temperature of hot and cold ions, angle of wave propagation, and mass, charge and temperature of the dust grains on the soliton characteristic is investigated in greater detail. The situation of electron-depleted plasma is also uncovered.

Withania somnifera (Ashwagandha) is a promising source of bioactive compounds and known for its medicinal properties for prehistoric times in India. The efficient and cost-effective extraction of bioactive compounds is the foremost step for drug development. The study was performed to evaluate the effect of selected solvents (hexane, chloroform, acetone, methanol, and aqueous) on the extraction yield, phytochemical composition, and antioxidant capacity of W. somnifera. Results showed that methanol followed aqueous extract is the most effective solvent with highest extraction yield (5.8%), phenolic content (85.88 mg GAE/g), and flavonoid content (105.09 mg QCE/g).The antioxidant activity was found to be effective in the order methanol > aqueous > acetone > chloroform > hexane extracts at different concentrations of 60240 μg/ml. TPC and TFC positively correlated with antioxidant activity, however, there is a strong correlation (

Multiple studies have associated the transcription factor IRF1 with tumor-suppressive activities. Here, we report an opposite tumor cell–intrinsic function of IRF1 in promoting tumor growth. IRF1-deficient tumor cells showed reduced tumor growth in MC38 and CT26 colon carcinoma and B16 melanoma mouse models. This reduction in tumor growth was dependent on host CD8+ T cells. Detailed profiling of tumor-infiltrating leukocytes did not show changes in the various T-cell and myeloid cell populations. However, CD8+ T cells that had infiltrated IRF1-deficieint tumors in vivo exhibited enhanced cytotoxicity. IRF1-deficient tumor cells lost the ability to upregulate PD-L1 expression in vitro and in vivo and were more susceptible to T-cell–mediated killing. Induced expression of PD-L1 in IRF1-deficient tumor cells restored tumor growth. These results indicate differential activity of IRF1 in tumor escape.