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We have shown previously that host adrenergic stress (model of standard ambient temperature-induced chronic stress) slows tumor progression by enhancing CD8+ T-cell activation and limiting the suppressive function of myeloid-derived suppressor cells in the tumor microenvironment (TME). We also found that reducing/blocking β-adrenergic receptor (β-AR) signaling significantly improves anti-tumor immune responses and efficacy of immune checkpoint immunotherapy. It has been reported that expression of immune checkpoint receptors (e.g. PD-1, TIM3, LAG3) is characteristic of exhausted T-cells and has been linked to failure of immune checkpoint inhibitors. Now we report that host adrenergic stress plays a previously unrecognized role in regulating T-cell exhaustion in the TME. In murine melanoma and colon cancer models, we found that propranolol (a pan β-AR blocker) significantly reduces the number of exhausted T-cells expressing immune checkpoint receptors in the TME and increases numbers of T-cells expressing effector cytokines. The overexpression of immune checkpoint receptors has also been associated with mitochondrial dysfunction. Our previous work shows that β-AR signaling during CD8+ T-cell activation in vitro impairs metabolic reprogramming. In new in vivo data, we observed that propranolol treatment increases both glycolysis and oxidative phosphorylation in tumor infiltrating CD8+ T-cells. Together these data suggest that β-AR signaling is a significant factor regulating the functional status of CD8+ T-cells in the TME. Blockade and/or reduction of adrenergic stress has the potential to improve anti-tumor immunity as well as the efficacy of immune checkpoint inhibitors.

AdaptMap Consortium.

Jointless stacked pancake (JSP) coils made by stacking double-slit YBCO tapes are the true sense of closed superconducting coils without any joints. This unique structure makes it a perfect alternative choice for the superconducting magnet in MRI/NRI. This paper focuses on magnetic field/current stability of JSP coil after partly thermal quenching. The experimental results show that the JSP coil has a certain field/current stability after partial quenching. In addition, the underlying physics of its field stability and the relationship between quenching power and stability time are concluded.

Persistent current switch (PCS) has become a common method to power the superconducting magnets because of its fast exciting speed and high-efficiency. This paper presents a general simulation mode, and the fundamental equations and exciting process of PCS exciting system are established. The simulation result shows great exciting effect. In addition, this paper reviews our three mainstream types of PCS: heat controlled PCS, current controlled PCS and magnetic field controlled PCS.

An immune response must be tightly controlled so that it will be commensurate with the level of response needed to protect the organism without damaging normal tissue. The roles of cytokines and chemokines in orchestrating these processes are well known, but although stress has long been thought to also affect immune responses, the underlying mechanisms were not as well understood. Recently, the role of nerves and, specifically, the sympathetic nervous system, in regulating immune responses is being revealed. Generally, an acute stress response is beneficial but chronic stress is detrimental because it suppresses the activities of effector immune cells while increasing the activities of immunosuppressive cells. In this review, we first discuss the underlying biology of adrenergic signaling in cells of both the innate and adaptive immune system. We then focus on the effects of chronic adrenergic stress in promoting tumor growth, giving examples of effects on tumor cells and immune cells, explaining the methods commonly used to induce stress in preclinical mouse models. We highlight how this relates to our observations that mandated housing conditions impose baseline chronic stress on mouse models, which is sufficient to cause chronic immunosuppression. This problem is not commonly recognized, but it has been shown to impact conclusions of several studies of mouse physiology and mouse models of disease. Moreover, the fact that preclinical mouse models are chronically immunosuppressed has critical ramifications for analysis of any experiments with an immune component. Our group has found that reducing adrenergic stress by housing mice at thermoneutrality or treating mice housed at cooler temperatures with β-blockers reverses immunosuppression and significantly improves responses to checkpoint inhibitor immunotherapy. These observations are clinically relevant because there are numerous retrospective epidemiological studies concluding that cancer patients who were taking β-blockers have better outcomes. Clinical trials testing whether β-blockers can be repurposed to improve the efficacy of traditional and immunotherapies in patients are on the horizon.

Additional file 15: Figure S8. Fraction of variance explained by repeated runs of Treemix software on the working dataset. Treemix software was run for a number of postulated migration edges, m, increasing from m0 to m11 (3 replicates per m).

Figure S1. Genetic relationships between individuals before and after removing closely related individuals. (A) genetic relationship in Laiwu pigs before removing closely related individuals; (B) genetic relationship in Laiwu pigs after removing closely related individuals; (C) genetic relationship in Yorkshire before removing closely related individuals; (D) genetic relationship in Yorkshire after removing closely related individuals. (PDF 15Â kb)

The host tolerance mechanisms to avian influenza virus (H5N1) infection that limit tissue injury remain unknown. Emerging evidence indicates that cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent Cl(-) channel, modulates airway inflammation. Janus tyrosine kinase (JAK) 3, a JAK family member that plays a central role in inflammatory responses, prominently contributes to the dysregulated innate immune response upon H5N1 attachment; therefore, this study aims to elucidate whether JAK3 activation induced by H5N1 hemagglutinin (HA) inhibits cAMP-dependent CFTR channels. We performed short-circuit current, immunohistochemistry and molecular analyses of the airway epithelium in Jak3(+/+) and Jak3(+/-) mice. We demonstrate that H5N1 HA attachment inhibits cAMP-dependent CFTR Cl(-) channels via JAK3-mediated adenylyl cyclase (AC) suppression, which reduces cAMP production. This inhibition leads to increased nuclear factor-kappa B (NF-κB) signaling and inflammatory responses. H5N1 HA is detected by TLR4 expressed on respiratory epithelial cells, facilitating JAK3 activation. This activation induces the interaction between TLR4 and Gαi protein, which blocks ACs. Our findings provide novel insight into the pathogenesis of acute lung injury via the inhibition of cAMP-dependent CFTR channels, indicating that the administration of cAMP-elevating agents and targeting JAK3 may activate host tolerance to infection for the management of influenza virus-induced fatal pneumonia.

Mice used for modeling cancer and anti-tumor immunity experience increased adrenergic stress due to IACUC-mandated cool housing temperatures. We wondered if this source of stress could be impacting the efficacy of ionizing radiation and the frequency of an “abscopal” effect (in which tumors outside the field of irradiation exhibit a response, an effect linked to enhanced systemic anti-tumor immunity). When mice bearing two separate CT26 tumors were housed at a thermoneutral temperature (TT; ~30°C) and 6 Gy of radiation was delivered to one tumor, control of both the irradiated and non-irradiated tumors was much greater than that seen in both tumors of mice housed at standard cool temperature (ST; ~22°C). Moreover, when tumor bearing mice housed at ST were treated with the pan β-blocker, propranolol and radiation, we observed a significantly improved growth control of irradiated and non-irradiated tumors. These effects were lost in SCID mice, and in mice depleted of CD8+T-cells. Experiments using knockout mice specifically identified a role for the β2 adrenergic receptor in mediating these effects. Moreover, we found that intra-tumoral effector T-cells, including IFN-γ+, GzmB+, TNFα+ and T-bet+CD8+T-cells, as well as the ratio of IFNγ+CD8+T-cells to Tregs, increased while numbers of MDSC and Tregs decreased, in mice treated with β-blocker and radiation. Finally, cured mice treated with propranolol and radiation rejected local and distant rechallenges in a tumor-specific manner. In conclusion, these data suggest that adrenergic stress plays a major role in regulating the efficacy of radiation therapy. Blockade of β2 adrenergic signaling could be a useful new strategy in the radiation oncology clinic.

CD8+T-cell activation requires a substantial up-regulation of both glycolysis and oxidative phosphorylation to support proliferation and immune effector functions. We have shown that chronic stress suppresses anti-tumor immunity and is associated with elevated levels of the sympathetic neurotransmitter norepinephrine (NE). NE signals through adrenergic receptors (ARs) present on all cells to coordinate a sympathetic stress response. We found that reducing or blocking AR signaling can significantly improve anti-tumor immune responses. Additionally, we discovered that triggering AR signaling during CD8+T-cell activation in vitro impairs metabolic reprogramming, primarily through the beta2-AR. We hypothesized that, in vivo, chronic stress would also impair metabolic reprogramming, leading to significant failure of intratumoral CD8+T-cell effector function. We found that the mitochondrial mass of CD8+T-cells isolated from B16-OVA tumors (melanoma) is decreased compared to CD8+T-cells from tumor draining lymph nodes; however, when tumor bearing WT mice are treated with propranolol, or in tumors grown in adrb2−/− mice, we found that tumor infiltrating CD8+T-cells have a higher mitochondrial mass. We also found that tumor infiltrating CD8+T-cells from mice treated with propranolol have higher CD28 expression, suggesting that adrenergic stress-induced signaling impairs metabolism of tumor infiltrating CD8+T-cells through a CD28-dependent pathway. Together, these data support the idea that in vivo, chronic stress inhibits the antitumor immune response through inhibition of CD8+T-cell metabolism.

While ionizing radiation is a major form of cancer therapy, radioresistance remains a therapeutic obstacle. We have previously shown that the mandated housing temperature for laboratory mice (~22°C) induces mild, but chronic, cold stress resulting in increased circulating norepinephrine, which binds to, and triggers activation of, beta-adrenergic receptors (β-AR) on tumor and immune cells. This adrenergic signaling increases tumor cell intrinsic resistance to chemotherapy and suppression of the anti-tumor immune response. These findings led us to hypothesize that adrenergic stress signaling increases radioresistance in tumor cells in addition to suppressing T-cell-mediated anti-tumor immunity, thus suppressing the overall sensitivity of tumors to radiation. We used three strategies to test the effect of adrenergic signaling on responsiveness to radiation. For one strategy, mice implanted with CT26 murine colon adenocarcinoma were housed at either 22°C or at thermoneutrality (30°C), which reduces physiological adrenergic stress. For a second strategy, we used a β-AR antagonist (“beta blocker”) to block adrenergic signaling in mice housed at 22°C. In either case, tumors were then irradiated with a single 6 Gy dose and the response was compared to mice whose adrenergic stress signaling was not reduced. For the third strategy, we used an in vitro approach in which several different tumor cell lines were treated with a β-AR agonist and irradiated, and cell survival was then assessed by clonogenic assay. Overall, we found that adrenergic stress significantly impaired the anti-tumor efficacy of radiation by inducing tumor cell resistance to radiation-induced cell killing and by suppression of anti-tumor immunity. Treatment using beta blockers is a promising strategy for increasing the anti-tumor efficacy of radiotherapy.

Background The identification of signals left by recent positive selection provides a feasible approach for targeting genomic variants that underlie complex traits and fitness. A better understanding of the selection mechanisms that occurred during the evolution of species can also be gained. In this study, we simultaneously detected the genome-wide footprints of recent positive selection that occurred within and between Chinese Holstein and Simmental populations, which have been subjected to artificial selection for distinct purposes. We conducted analyses using various complementary approaches, including LRH, XP-EHH and FST, based on the Illumina 770K high-density single nucleotide polymorphism (SNP) array, to enable more comprehensive detection. Results We successfully constructed profiles of selective signals in both cattle populations. To further annotate these regions, we identified a set of novel functional genes related to growth, reproduction, immune response and milk production. There were no overlapping candidate windows between the two breeds. Finally, we investigated the distribution of SNPs that had low FST values across five distinct functional regions in the genome. In the low-minor allele frequency bin, we found a higher proportion of low-FST SNPs in the exons of the bovine genome, which indicates strong purifying selection of the exons. Conclusions The selection signatures identified in these two populations demonstrated positive selection pressure on a set of important genes with potential functions that are involved in many biological processes. We also demonstrated that in the bovine genome, exons were under strong purifying selection. Our findings provide insight into the mechanisms of artificial selection and will facilitate follow-up functional studies of potential candidate genes that are related to various economically important traits in cattle. Electronic supplementary material The online version of this article (doi:10.1186/s12711-016-0254-5) contains supplementary material, which is available to authorized users.

Seamoth (Pegasus laternarius Cuvier) is extensively used to treat various diseases on the coastland of Guangdong Province in China, such as scrofula, cough, and diarrhea. The total extract of Pegasus laternarius (EP) was subjected to column chromatography to acquire three different constituents (EPC1, EPC2, and EPC3). Cerebral neuron injury was induced by glutamate, H₂O₂, and serum deprivation. After treating with or without different extracts, cell viability was assessed with the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and cell apoptosis was analyzed with Hoechst 33258 staining and agarose gel electrophoresis. We also determined the levels of lactate dehydrogenase (LDH), maleic dialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px). The results showed that both EP and EPC2 promoted the outgrowth of cultural neurons, increased antioxidant enzyme activity, and protected neurons from neuronal injury or apoptosis induced by glutamate, H₂O₂, and serum deprivation. EPC1 and EPC3 had little or no effect on neurons. These results suggest that the active ingredients obtained from Pegasus laternarius have potential neuroprotective effects on injured neurons by promoting the outgrowth of cultured neurons, increasing the activity of intracellular antioxidants, and exerting antiapoptotic effects. This neuroprotection may be attributable to specific active ingredients, such as taurine, novel ceramide, and cholesterol.

Additional file 7: Figure S6. Genome-wide distribution of 500-kb window-based maximum |XP-EHH| and average FST. The dash line indicates the threshold for the FST test.

Supplementary material, approximately 434 KB.

Obesity compromises bone marrow (BM) progenitor function and the mechanistic underpinnings are just beginning to be established. Here we show that following 16 weeks of high fat diet, mice exhibit poor emergency hematopoiesis in a toll-like receptor 4 (TLR4)-dependent manner, and that adoptive transfer of obese BM to lean recipients restores rebound capability. Genes associated with a myeloid signature (c-fms, pu.1, ikaros) are enhanced and lymphoid signature (flt3, meis1, e47) reduced. The skewed lympho-myeloid outgrowth of discrete BM subsets is apparent by 6 weeks of high fat diet, earlier than is commonly recognized. Using mixed BM chimeras we demonstrate that obesity-associated subversion of lineage-c-kit+Sca-1- (LKSneg) precursors to the myeloid lineage and common lymphoid progenitors (CLP) to the B lineage depends on BM cell subset-autonomous TLR4. The endogenous TLR4 ligands responsible for BM dysfunction in obesity are unclear. Here, we show that exposure of lean mice to lipopolysaccharide (LPS) at levels similar to that observed in obesity recapitulates key aspects of BM lympho-myeloid disruption. Together, our results establish a mechanistic role for BM cell-intrinsic TLR4 early in obesity-driven BM dysfunction, and demonstrate the biological importance of one obesity-associated TLR4 ligand.

DNA repair capacity is central in maintaining normal cellular functions. Variants of several DNA repair genes,including the nucleotide excision repair gene XPD, have been described recently. Because we previously reported that patients with squamous cell carcinoma of the head and neck (SCCHN) had lower DNA repair capacity than healthy controls, we hypothesized that inherited polymorphisms of XPD may contribute to genetic susceptibility to SCCHN, a tobacco-related cancer. To test this hypothesis, we conducted a hospital-based case-control study of 189 SCCHN patients and 496 cancer-free controls who were frequency-matched on age, gender and smoking status. All subjects were non-Hispanic whites. Two XPD polymorphisms (C22541A and A35931C) were typed using the restriction enzymes TfiI and PstI, respectively. Multivariate logistic regression analysis was performed to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). In the controls, the frequencies of the variant 22541A and 35931C alleles were 44.7% and 33.8%, respectively. The frequency of the 22541A homozygous genotype (22541AA) was lower in cases (15.9%) than in controls (20.4%) but was not associated with risk (adjusted OR = 0.90; 95% CI = 0.52-1. 56) for SCCHN. The frequency of the 35931C homozygous genotype (35931CC) was higher in cases (16.4%) than in controls (11.5%) and associated with a borderline increased risk (adjusted OR = 1.55; 95% CI = 0.96-2.52) for SCCHN. The risk was higher in older subjects (OR = 2.22; 95% CI = 1.03-4.80), current smokers (OR = 1.83; 95% CI = 0.79-4.27) and current drinkers (OR = 2.59; 95% CI = 1.25-5.34) in the stratification analysis. These results suggest a gene-environment interaction, but this did not reach statistical significance. The findings are limited due to the relatively small numbers in the subgroups and need to be verified by further investigations.

OBJECTIVE To establish a HPLC method with the relative correction factors (RCFs) for quantification of five critical related substances (A, B, C, D and E) in puerarin and its injection. METHOD Taking puerarin as the internal standard, corresponding RCFs of the critical related substances were determined respectively. According to their RCFs, simultaneous determination of five related substances in puerarin and its injection was performed. The method was evaluated by comparison the quantitative results of external standard method and the method with RCFs correction. RESULT There were no significant differences in the results of five critical related substances in 38 batches of puerarin and its injection by external standard method and the method with RCFs correction. CONCLUSION The HPLC method with RCFs was validated to be accurate and can be successfully applied to determine the critical related substances in puerarin and its injection.

There are some indications thtt herpes simplex virus (HSV) may be mutagenic. Specific chromosomal changes have also been demonstrated in cultured cells infected with HSV. To further investigate the mutagenic activity of HSV type 2 (HSV-2) we used mouse skin as a model system for carcinogenesis. Inoculation of the back skin of 4-week-old Sencar mice with live virus twice per week for one week or with inactivated virus twice per week for two weeks was used to initiate the mouse skin. After initiation with HSV-2, 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied twice weekly for 50 weeks as a promoter. During a period of 52 weeks, no skin carcinoma was found in the experimental groups, whereas 55% of control mice treated with 9, 10-dimethyl-1, 2-benzanthracene (DMBA) and then with TPA-developed skin carcinoma. The results demonstrate that HSV-2 could not substitute for DMBA in this animal model of two-stage skin carcinogenesis.

The aim of this study was to investigate the functional expression of cystic fibrosis transmembrane conductance regulator (CFTR) with electrophysiological and molecular technique in rat oviduct epithelium. In whole-cell patch clamp, oviduct epithelial cells responded to 100 microM 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) with a rise in inward current in Gap-free mode, which was inhibited successively by 5 microM CFTR(inh)-172, a CFTR specific inhibitor, and 1 mM diphenylamine-2-carboxylate (DPC), the Cl- channel blocker. The cAMP-activated current exhibited a linear current-voltage (I-V) relationship and time- and voltage-independent characteristics. The reversal potentials of the cAMP-activated currents in symmetrical Cl- solutions were close to the Cl- equilibrium, 0.5+/-0.2 mV (n=4). When Cl- concentration in the bath solution was changed from 140 mM to 70 mM and a pipette solution containing 140 mM Cl- was used, the reversal potential shifted to a value close to the new equilibrium for Cl-, 20+/-0.6 mV (n=4), as compared with the theoretic value of 18.7 mV. In addition, mRNA expression of CFTR was also detected in rat oviduct epithelium. Western blot analysis showed that CFTR protein is found in the oviduct throughout the cycle with maximal expression at estrus, and immunofluorescence and immunohistochemistry analysis revealed that CFTR is located at the apical membrane of the epithelial cells. These results showed that the cAMP-activated Cl- current in the oviduct epithelium was characteristic of CFTR, which provided direct evidence for the functional expression of CFTR in the rat oviduct epithelium. CFTR may play a role in modulating fluid transport in the oviduct.

Light-induced autofluorescence spectra of nasopharyngeal carcinoma and normal tissue in vitro were compared to that of known endogenous fluorophores to explore the possible causes of tissue autofluorescence and to further determine the optimal excitation wavelengths for optical biopsy in vivo. Nasopharyngeal carcinoma and normal tissues were obtained from the suspected patients during pathological biopsy. A FL/FS92O combined TCSPC spectrofluonmeter and a lifetime spectrometer system was used for autofluorescence spectra measurement. Fluorescence excitation wavelengths varying from 260 to 480 nm were used to induce tissue autofluorescence, and the corresponding fluorescence emission spectra were recorded from a range starting 20 nm above the excitation wavelength and extending to 700 nm. The autofluorescence excitation-emission pairs of nasopharyngeal carcinoma and nonnal tissues occur at 300-330, 340-460 and 450-520 nm, and the optimal diagnostic excitation wavelengths for detection of nasopharyngeal carcinoma were 340 and 450 nm. The results abtained in this study could be treated as a reference for the development of optical biopsy system for nasopharyngeal carcinoma.