Tetrabromobisphenol A exerts thyroid disrupting effects but has little overt impact on postnatal brain development and neurobehaviors in mice.

Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant. There is evidence showing that TBBPA can exert thyroid disrupting effects in mammals, but different results were also reported, along with inconsistent reports regarding its neurotoxicity. Here, we investigated thyroid disrupting effects and neurotoxicity of TBBPA (5, 50, 500 µg/(kg·day)) to male mice following maternal and direct exposure through drinking water, with the anti-thyroid drug propylthiouracil (PTU) as the positive control. On postnatal day (PND) 15, we expectedly observed severe thyroid compensatory hyperplasia and cerebellar developmental retardation in PTU-treated pups. The highest dose of TBBPA also caused thyroid histological alteration but had no effects on cerebellar development in terms of Purkinje cell morphology and the thickness of the internal granular layer and the molecular layer of the cerebellum. During puberty and adulthood, the thyroid morphological alterations became more pronounced in the TBBPA-treated animals, accompanied by decreased serum thyroid hormone levels. Furthermore, the 50 and 500 µg/(kg·day) TBBPA groups showed a significant decrease in the serum level of serotonin, a neurotransmitter associated with anxiety behaviors. Correspondingly, the highest dose group displayed anxiety-like behaviors in the elevated plus-maze test on PND 35, but this neurobehavioral alteration disappeared on PND 56. Moreover, no changes in neurobehavioral parameters tested were found in TBBPA-treated animals at puberty and adulthood. Altogether, all observations show that TBBPA can exert thyroid disrupting effects but has little overt impact on brain development and neurobehaviors in mice, suggesting that thyroid disruption does not necessarily cause overtly adverse neurodevelopmental outcomes.

γ-Glutamylcysteine ameliorates blood-brain barrier permeability and neutrophil extracellular traps formation after ischemic stroke by modulating Wnt/ß-catenin signalling in mice.

During the inflammatory response after stroke, the blood-brain barrier (BBB) is significantly disrupted, compromising its integrity. This disruption allows many peripheral neutrophils to infiltrate the injury site in the brain and release neutrophil extracellular traps (NETs), which further increase BBB permeability. In this study, we aimed to investigate the protective effects of γ-Glutamylcysteine (γ-GC), an immediate precursor of GSH, against BBB breakdown and NET formation after ischemic stroke. Our data indicated that γ-GC treatment effectively attenuated BBB damage, decreased neutrophil infiltration, and suppressed the release of NETs, ultimately leading to the amelioration of ischemic injury. Transcriptomic data and subsequent validation studies revealed that mechanistically, γ-GC exerts its effect by activating the Wnt/ß-catenin pathway after ischemic stroke. This research suggests that γ-GC may hold promise as a therapeutic agent for alleviating brain injury following an ischemic stroke.

Modeling drug-induced mitochondrial toxicity with human primary cardiomyocytes.

Mitochondrial toxicity induced by therapeutic drugs is a major contributor for cardiotoxicity, posing a serious threat to pharmaceutical industries and patients' lives. However, mitochondrial toxicity testing is not incorporated into routine cardiac safety screening procedures. To accurately model native human cardiomyocytes, we comprehensively evaluated mitochondrial responses of adult human primary cardiomyocytes (hPCMs) to a nucleoside analog, remdesivir (RDV). Comparison of their response to human pluripotent stem cell-derived cardiomyocytes revealed that the latter utilized a mitophagy-based mitochondrial recovery response that was absent in hPCMs. Accordingly, action potential duration was elongated in hPCMs, reflecting clinical incidences of RDV-induced QT prolongation. In a screen for mitochondrial protectants, we identified mitochondrial ROS as a primary mediator of RDV-induced cardiotoxicity. Our study demonstrates the utility of hPCMs in the detection of clinically relevant cardiac toxicities, and offers a framework for hPCM-based high-throughput screening of cardioprotective agents.

GM-CSF Promotes the Development of Dysfunctional Vascular Networks in Moyamoya Disease.

Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease with the development of a network of abnormal vessels. Immune inflammation is associated with the occurrence and development of MMD. However, the mechanisms underlying the formation of the abnormal vascular network remain unclear. Twenty-eight patients with MMD, 26 ischemic stroke patients, and 26 unrelated healthy volunteers were enrolled in this study The data showed that the levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) were higher in MMD patients than in healthy controls (P <0.01), and GM-CSF was mainly from Th1 and Th17 cells in MMD. We found that increased GM-CSF drove monocytes to secrete a series of cytokines associated with angiogenesis, inflammation, and chemotaxis. In summary, our findings demonstrate for the first time the important involvement of GM-CSF in MMD and that GM-CSF is an important factor in the formation of abnormal vascular networks in MMD.

Infiltrating myeloid cell-derived properdin markedly promotes microglia-mediated neuroinflammation after ischemic stroke.

BACKGROUND: Emerging evidence has shown that myeloid cells that infiltrate into the peri-infarct region may influence the progression of ischemic stroke by interacting with microglia. Properdin, which is typically secreted by immune cells such as neutrophils, monocytes, and T cells, has been found to possess damage-associated molecular patterns (DAMPs) properties and can perform functions unrelated to the complement pathway. However, the role of properdin in modulating microglia-mediated post-stroke neuroinflammation remains unclear. METHODS: Global and conditional (myeloid-specific) properdin-knockout mice were subjected to transient middle cerebral artery occlusion (tMCAO). Histopathological and behavioral tests were performed to assess ischemic brain injury in mice. Single-cell RNA sequencing and immunofluorescence staining were applied to explore the source and the expression level of properdin. The transcriptomic profile of properdin-activated primary microglia was depicted by transcriptome sequencing. Lentivirus was used for macrophage-inducible C-type lectin (Mincle) silencing in microglia. Conditioned medium from primary microglia was administered to primary cortex neurons to determine the neurotoxicity of microglia. A series of cellular and molecular biological techniques were used to evaluate the proinflammatory response, neuronal death, protein-protein interactions, and related signaling pathways, etc. RESULTS: The level of properdin was significantly increased, and brain-infiltrating neutrophils and macrophages were the main sources of properdin in the ischemic brain. Global and conditional myeloid knockout of properdin attenuated microglial overactivation and inflammatory responses at the acute stage of tMCAO in mice. Accordingly, treatment with recombinant properdin enhanced the production of proinflammatory cytokines and augmented microglia-potentiated neuronal death in primary culture. Mechanistically, recombinant properdin served as a novel ligand that activated Mincle receptors on microglia and downstream pathways to drive primary microglia-induced inflammatory responses. Intriguingly, properdin can directly bind to the microglial Mincle receptor to exert the above effects, while Mincle knockdown limits properdin-mediated microglial inflammation. CONCLUSION: Properdin is a new medium by which infiltrating peripheral myeloid cells communicate with microglia, further activate microglia, and exacerbate brain injury in the ischemic brain, suggesting that targeted disruption of the interaction between properdin and Mincle on microglia or inhibition of their downstream signaling may improve the prognosis of ischemic stroke.

Analysis of metal(loid) pollution and possibilities of electrokinetic phytoremediation of abandoned coking plant soil.

In this study, the spatial distribution of eight metal(loid)s in the soil of an abandoned coking plant in Shanxi, China, was mapped, and the ecological and health risks of the coking plant were assessed. The results showed that the soil Pb content of the coking plant greatly exceeded the background value, and Hg, Cd and Pb were the most polluting factors contributing to the considerable ecological risk level. There was also a non-carcinogenic risk in the coking plant, in which oral intake was the main pathway, and As, Pb and Cr were the main contributors. As the main contributor to ecological risk and non-carcinogenic risks and the most polluting metal, Pb was selected as a priority pollutant in the coking plant. Based on the detected concentration of Pb in the coking plant soil and in consideration of phytostabilization, ryegrass, alfalfa and castor were employed to study the phytoremediation and electrokinetic-enhanced phytoremediation effect in a series of Pb-contaminated soils (0, 100, 200, 300 and 400 mg/kg). It was found that the underground parts of alfalfa and castor had stronger Pb enrichment ability, and their biomass and Pb absorption capacity were improved in electrokinetic remediation methods. The Pb absorption capacities of the tested plants and the promotion efficiencies of electrokinetic-enhanced phytoremediation followed the order castor > ryegrass > alfalfa. Under the optimal electrical conditions, the remediation efficiency of castor was increased by 106 %, 83 %, 51 % and 48 % in 100, 200, 300, and 400 mg/kg Pb-contaminated soils, respectively.

Effect of distributed Bragg reflectors on photoluminescence properties of CH3NH3PbI3 film.

The nanoporous (NP) GaN distributed Bragg reflector (DBR) was prepared by using electrochemical etching. Then the NP-GaN DBR was pretreated by using ozone treatment. Atomic force microscopy and X-ray diffraction (XRD) were used to investigate the influence of ozone treatment on the structure of the substrates. The hybrid organic-inorganic CH3NH3PbI3 perovskite films were grown on the NP-GaN DBR and reference substrates by using a one-step solution method. The XRD and field emission scanning electron microscopy test results indicate the high quality of the prepared CH3NH3PbI3 perovskite films. The photoluminescence intensity of the prepared CH3NH3PbI3 perovskite film on the NP-GaN DBR substrate is ~ 3.5 times higher than that of the film on the reference substrate, with a 3.6 nm spectral blue-shift. The enhancement should be contributable to amplify spontaneous emission by resonant cavity, while the blue-shift could be contributable to stoichiometric difference of the films on different substrates.

Bisphenol chemicals disturb intestinal homeostasis via Notch/Wnt signaling and induce mucosal barrier dysregulation and inflammation.

Emerging evidence has shown that bisphenol A (BPA) can exert adverse effects on intestinal barrier in rodents, but little is known about its underlying mechanisms. We previously found BPA and its substitute bisphenol F (BPF) disrupted Notch signaling and altered intestinal histological structures in Xenopus laevis tadpoles. The present study aimed to determine whether BPA and BPF could affect intestinal homeostasis via Notch/Wnt signaling and induce intestinal barrier dysregulation in adult mammals, given the fundamental roles of the two conserved signaling pathways in intestinal homeostasis and regulation of intestinal barrier. We found that following 7-day administration with BPA or BPF through drinking water at the reference dose of 50 µg/kg/d and no observed adverse effect level of 5 mg/kg/d (NOAEL) of BPA, adult male mice displayed no alterations at histological and cellular levels in colons, but high dose of both BPA and BPF downregulated the expression of Notch- and Wnt-related genes as well as key genes responsible for intestinal homeostasis. When administration was extended to 14 days, all treatments significantly suppressed the expression of all tested Notch- and Wnt-related genes; correspondingly, administrated colons exhibited downregulated expression of key genes responsible for intestinal homeostasis and reduced cell proliferation in crypts. Importantly, all treatments suppressed secretory cell differentiation, reduced mucin protein levels and downregulated expression of tight junction markers, implicating mucosal barrier dysregulation. Furthermore, inflammatory cell infiltration and upregulated expression of inflammatory cytokine genes in colons, coupled with increased serum inflammatory cytokine levels, were observed in all treatments. All results show that both BPA and BPF at the reference dose disrupted Notch/Wnt signaling and intestinal homeostasis, thereby leading to mucosal barrier dysregulation and intestinal inflammation in mice. This is the first study revealing the adverse influences of BPF on mammal intestines and underlying mechanisms for bisphenol-caused intestinal injury.

Effects of postnatal exposure to tetrabromobisphenol A on testis development in mice and early key events.

Whether or not tetrabromobisphenol A (TBBPA) has reproductive developmental toxicity remains controversial. Here, we evaluated the effects of postnatal TBBPA exposure of dams (before weaning) and pups through drinking water (15, 150, 1500 ng/mL) on testis development in mice. On postnatal day (PND) 56, we found that TBBPA exerted little effects on testis weight, anogenital distance, sperm parameters, and the serum testosterone level, but resulted in dose-dependent reductions in the seminiferous tubule area coupled with decreased Sertoli cells and spermatogonia and the number of stage VII-VIII seminiferous tubules, and cytoskeleton damage in Sertoli cells, along with down-regulated expression of marker genes for Sertoli cells, spermatogonia and spermatocyte. Further study revealed that the reduced tubule area coupled decreased Sertoli cell and germ cell numbers and marker gene expression also occurred in TBBPA-treated testes on PND 7, along with reduced cell proliferation and disordered arrangement of Sertoli cell nuclei. On PND 15, most of these testicular alterations were still observed in TBBPA-treated males, and cytoskeleton damage in Sertoli cells became observable. All observations convincingly demonstrate that postnatal exposure to TBBPA disturbed testis development in early life and ultimately caused adverse outcomes in adult testes, and that cell proliferation inhibition, the reduction in the seminiferous tubule area coupled decreased Sertoli cell and germ cell numbers and marker gene expression, and cytoskeleton damage in Sertoli cells, are early events contributing to adverse outcomes in adult testes. Our study improves the understanding of reproductive developmental toxicity of TBBPA, highlighting its risk for human health.

The ICOS-ICOSL pathway tunes thymic selection.

Negative selection of developing T cells plays a significant role in T-cell tolerance to self-antigen. This process relies on thymic antigen-presenting cells which express both self-antigens and cosignaling molecules. Inducible T-cell costimulator (ICOS) belongs to the CD28 family of cosignaling molecules and binds to ICOS ligand (ICOSL). The ICOS signaling pathway plays important roles in shaping the immune response to infections, but its role in central tolerance is less well understood. Here we show that ICOSL is expressed by subsets of thymic dendritic cells and medullary thymic epithelial cells as well as thymic B cells. ICOS expression is upregulated as T cells mature in the thymus and correlates with T-cell receptor signal strength during thymic selection. We also provide evidence of a role for ICOS signaling in mediating negative selection. Our findings suggest that ICOS may fine-tune T-cell receptor signals during thymic selection contributing to the generation of a tolerant T-cell population.

A strategy of vascular-targeted therapy for liver fibrosis.

BACKGROUND AND AIMS: No effective treatments are available for liver fibrosis. Angiogenesis is deeply involved in liver fibrogenesis. However, current controversial results suggest it is difficult to treat liver fibrosis through vascular targeting. There are three different microvessels in liver: portal vessels, liver sinusoids, and central vessels. The changes and roles for each of the three different vessels during liver fibrogenesis are unclear. We propose that they play different roles during liver fibrogenesis, and a single vascular endothelial cell (EC) regulator is not enough to fully regulate these three vessels to treat liver fibrosis. Therefore, a combined regulation of multiple different EC regulatory signaling pathway may provide new strategies for the liver fibrosis therapy. Herein, we present a proof-of-concept strategy by combining the regulation of leukocyte cell-derived chemotaxin 2 (LECT2)/tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 signaling with that of vascular endothelial growth factor (VEGF)/recombinant VEGF (rVEGF) signaling. APPROACH AND RESULTS: The CCl4 -induced mouse liver fibrosis model and NASH model were both used. During fibrogenesis, vascular changes occurred at very early stage, and different liver vessels showed different changes and played different roles: decreased portal vessels, increased sinusoid capillarization and the increased central vessels the increase of portal vessels alleviates liver fibrosis, the increase of central vessels aggravates liver fibrosis, and the increase of sinusoid capillarization aggravates liver fibrosis. The combinational treatment of adeno-associated viral vector serotype 9 (AAV9)-LECT2-short hairpin RNA (shRNA) and rVEGF showed improved therapeutic effects, but it led to serious side effects. The combination of AAV9-LECT2-shRNA and bevacizumab showed both improved therapeutic effects and decreased side effects. CONCLUSIONS: Liver vascular changes occurred at very early stage of fibrogenesis. Different vessels play different roles in liver fibrosis. The combinational treatment of AAV9-LECT2-shRNA and bevacizumab could significantly improve the therapeutic effects on liver fibrosis.

Developing the right tools for the job: Lin28 regulation of early life T-cell development and function.

T cells comprise a functionally heterogeneous cell population that has important roles in the immune system. While T cells are broadly considered to be a component of the antigen-specific adaptive immune response, certain T-cell subsets display innate-like effector characteristics whereas others perform immunosuppressive functions. These functionally diverse T-cell populations preferentially arise at different stages of ontogeny and are tailored to the immunological priorities of the organism over time. Many differences in early life versus adult T-cell phenotypes can be attributed to the cell-intrinsic properties of the distinct progenitors that seed the thymus throughout development. It is becoming clear that Lin28, an evolutionarily conserved, heterochronic RNA-binding protein that is differentially expressed among early life and adult hematopoietic progenitor cells, plays a substantial role in influencing early T-cell development and function. Here, we discuss the mechanisms by which Lin28 shapes the T-cell landscape to protect the developing fetus and newborn. Manipulation of the Lin28 gene regulatory network is being considered as one means of improving hematopoietic stem cell transplant outcomes; as such, understanding the impact of Lin28 on T-cell function is of clinical relevance.

Photosynthesis of winter wheat effectively reflected multiple physiological responses under short-term drought-rewatering conditions.

BACKGROUND: Based on the interrelationship among photosynthesis (Pn), water consumption and drought resistance physiology under water changes, this study aimed to explore whether easily measured Pn could be used to reflect the physiological state of winter wheat and soil moisture. The study was a greenhouse pot experiment, with three growth periods and four gradients of moisture. RESULTS: The instantaneous water use efficiency of wheat improved significantly under short-term regulated deficit irrigation conditions. The photosynthetic parameters could effectively reflect the level of soil moisture (receiver operating characteristic curve analysis, area under the curve = 0.683-0.988). There was a significant correlation between Pn and yield under drought and rewatering (P < 0.05). The water consumption of winter wheat was significantly reduced by 15.5% to 47.6% (P < 0.05) during drought owing to the reduction of stomatal conductance and transpiration rate (Tr). There was a significant linear relationship between Tr and daily water consumption (R2 > 0.745, P< 0.05). There was a significant quadratic linear relationship (R2 > 0.600, P < 0.05) between Pn and the drought resistance indicators. The protective effect of drought resistance physiology on Pn was more significant during drought than during rewatering. Among the four physiological indicators of drought resistance, the relationship between peroxidase activity and Pn was relatively close (grey relational analysis, GRO = 1). CONCLUSIONS: The photosynthetic parameters during conditions of short-term water changes could effectively reflect the status of soil moisture, water consumption, yield and drought resistance. A focus on Pn and the rational use of related relationships are conducive to the selection of drought-resistant varieties and developing refined agricultural management. © 2021 Society of Chemical Industry.

Tetrabromobisphenol A: a neurotoxicant or not?

Although some regulatory agencies have claimed that consumer exposures to tetrabromobisphenol A (TBBPA) are not likely to cause adverse health effects in humans or the environment, the safety of tetrabromobisphenol A (TBBPA) has been questioned. Here, we summarize the literature concerning in vivo and in vitro neurotoxicity of TBBPA over the past decades. Most laboratory rodent studies reported that gavage administration of TBBPA at doses below 1000 mg/kg/day generally exerted no or limited effects on neuropathology and locomotor behaviors, but increased anxiety and auditory impairments were observed in several studies. In fish and amphibians, waterborne exposure to TBBPA was generally reported to disrupt neurodevelopment and lead to neurobehavioral alterations. Moreover, in vitro studies support the observations that TBBPA could exert neurotoxic effects in vertebrates. Thus, we suggest that TBBPA could have adverse effects on the nervous system in vertebrates. Given rapid excretion and low availability of TBBPA in laboratory rodents following single gavage administration, we speculate that single-daily gavage could result in an underestimation of the neurotoxic effects of TBBPA in rodents. Thus, we propose to employ multiple-daily administration routes (such as dermal, inhalation, and drinking water), to further assess the neurotoxic effects of TBBPA in mammals.

Measurement of polychlorinated biphenyls with hand wipes and matched serum collected from Chinese E-waste dismantling workers: Exposure estimates and implications.

To date, dermal/hand-to-mouth exposure to chemicals in the e-waste recycling environment has not been sufficiently understood, and the importance of dermal absorption of chemicals in e-waste dismantling workers remains controversial. In this study, we utilized hand wipes and matched sera to characterize dermal/hand-to-mouth exposure to PCBs for e-waste dismantling workers, and potential effects on thyroid hormones were also assessed. PCB loadings in hand wipes varied from 0.829-265 ng wipe-1 (11.3-2850 ng m-2 wipe-1), with 37.2 ng wipe-1 (432 ng m-2 wipe-1) as the median value. Serum concentrations of PCBs ranged from 32.3-3410 ng g-1 lipid weight (lw) with 364 ng g-1 lw as the median value. Between wipes and sera, lower-chlorinated congeners (e.g. CB-28, -66, -74, -99,-105 and -118) showed significant associations (p < 0.01), but higher-chlorinated congeners (e.g. CB-138, -153, -156, -170, and -180) did not. These lower-chlorinated CBs were the major contributors to estimated dermal/hand-to-mouth average daily doses (ADDs) and the hazard index (HI). Correspondingly, their estimated contributions to serum levels by dermal absorption were also significant, with the contribution of CB-28 being as high as 21.4%. As a consequence, dermal absorption of some low-chlorinated congeners was a non-negligible route for e-waste dismantling workers. Although insignificant association was shown between serum PCBs and thyroid hormones, the potential health risk should be of concern due to the high levels of PCBs observed in workers' sera.

Bisphenols disrupt thyroid hormone (TH) signaling in the brain and affect TH-dependent brain development in Xenopus laevis.

There is concern about adverse effects of thyroid hormone (TH) disrupting chemicals on TH-dependent brain development. Bisphenol A (BPA) and its analogues, such as bisphenol F (BPF), are known to have the potential to interfere with TH signaling, but whether they affect TH-dependent brain development is not yet well documented. Here, we conducted the T3-induced Xenopus laevis metamorphosis assay, a model for studying TH signaling disruption, to investigate the effects of BPA and BPF (10-1000 nM) on TH signaling in brains and subsequent brain development. While 48-hr treatment with 1 nM T3 dramatically upregulated TH-response gene expression in X. laevis brains at stage 52, 1000 and/or 100 nM BPA also caused significant transcriptional up-regulation of certain TH-response genes, whereas BPF had slighter effects, suggesting limited TH signaling disrupting activity of BPF in brains relative to BPA at the lack of TH. In the presence of 1 nM T3, 1000 and/or 100 nM of BPF as well as BPA antagonized T3-induced TH-response gene expression, whereas lower concentrations agonized T3 actions on certain TH-response genes, displaying an apparently biphasic effect on TH signaling. After 96 h exposure, T3 induced brain morphological remodeling coupled with cell proliferation and neuronal differentiation, whereas both BPA and BPF generally antagonized T3-induced changes in a concentration-dependent manner, with weak or no effects of bisphenol exposure alone. Overall, all results show that BPA and BPF interfered with TH signaling in Xenopus brains, especially in the presence of TH, and subsequently affected TH-dependent brain development. Given the evolutionary conservation of TH-dependent brain development among vertebrates, our findings from X. laevis warrant further studies to reveal potential influences of bisphenols on TH-dependent brain development in higher vertebrates.

Signal intensity ratio of draining vein on silent MR angiography as an indicator of high-flow arteriovenous shunt in brain arteriovenous malformation.

OBJECTIVES: To evaluate whether the signal intensity ratio (rSI) of the draining vein on silent MR angiography is correlated with arteriovenous (A-V) transit time on digital subtraction angiography (DSA), thereby identifying high-flow A-V shunt in brain arteriovenous malformation (BAVM), and to analyze whether the rSI and the characteristic of draining veins on silent MRA are associated with hemorrhage presentation. METHODS: Eighty-one draining veins of 46 participants with BAVM (mean age 33.2 ± 16.9 years) who underwent silent MRA and DSA were evaluated retrospectively. The correlation between the rSI of the draining vein on silent MRA and A-V transit time on DSA was examined. The AUC-ROC was obtained to evaluate the performance of the rSI in determining the presence of high-flow A-V shunt. The characteristics of draining veins with the maximum rSI (rSImax) were further compared between the hemorrhagic and non-hemorrhagic untreated BAVM. RESULTS: The rSI of each draining vein on silent MRA was significantly correlated with A-V transit time from DSA (r = -0.81, p < .001). The AUC-ROC was 0.89 for using the rSI to determine the presence of high-flow A-V shunt. A cut-off rSI value of 1.09 yielded a sensitivity of 82.4% and a specificity of 82.8%. The draining vein with rSImax and no ectasia was significantly more observed in the hemorrhagic group (p = 0.045). CONCLUSIONS: The rSI of the draining vein on silent MRA is significantly correlated with A-V transit time on DSA, and it can be used as an indicator of high-flow A-V shunt in BAVM. KEY POINTS: • The signal intensity ratio (rSI) of the draining vein on silent MRA significantly correlated with arteriovenous (A-V) transit time of brain arteriovenous malformation (BAVM) on digital subtraction angiography (DSA). • The area under the receiver operating characteristic curve (AUC) was 0.89 for using the rSI of draining veins to determine high-flow A-V shunt. • Draining veins with maximum rSI and no ectasia were significantly more observed in the hemorrhagic group of BAVM (p = 0.045).

NR4A3 Mediates Thymic Negative Selection.

Central tolerance aims to limit the production of T lymphocytes bearing TCR with high affinity for self-peptide presented by MHC molecules. The accumulation of thymocytes with such receptors is limited by negative selection or by diversion into alternative differentiation, including T regulatory cell commitment. A role for the orphan nuclear receptor NR4A3 in negative selection has been suggested, but its function in this process has never been investigated. We find that Nr4a3 transcription is upregulated in postselection double-positive thymocytes, particularly those that have received a strong selecting signal and are destined for negative selection. Indeed, we found an accumulation of cells bearing a negative selection phenotype in NR4A3-deficient mice as compared with wild-type controls, suggesting that Nr4a3 transcriptional induction is necessary to limit accumulation of self-reactive thymocytes. This is consistent with a decrease of cleaved caspase-3+-signaled thymocytes and more T regulatory and CD4+Foxp3-HELIOS+ cells in the NR4A3-deficient thymus. We further tested the role for NR4A3 in negative selection by reconstituting transgenic mice expressing the OVA Ag under the control of the insulin promoter with bone marrow cells from OT-I Nr4a3 +/+ or OT-I Nr4a3 -/- mice. Accumulation of autoreactive CD8 thymocytes and autoimmune diabetes developed only in the absence of NR4A3. Overall, our results demonstrate an important role for NR4A3 in T cell development.

CD5 levels define functionally heterogeneous populations of naïve human CD4+ T cells.

Studies in murine models show that subthreshold TCR interactions with self-peptide are required for thymic development and peripheral survival of naïve T cells. Recently, differences in the strength of tonic TCR interactions with self-peptide, as read-out by cell surface levels of CD5, were associated with distinct effector potentials among sorted populations of T cells in mice. However, whether CD5 can also be used to parse functional heterogeneity among human T cells is less clear. Our study demonstrates that CD5 levels correlate with TCR signal strength in human naïve CD4+ T cells. Further, we describe a relationship between CD5 levels on naïve human CD4+ T cells and binding affinity to foreign peptide, in addition to a predominance of CD5hi T cells in the memory compartment. Differences in gene expression and biases in cytokine production potential between CD5lo and CD5hi naïve human CD4+ T cells are consistent with observations in mice. Together, these data validate the use of CD5 surface levels as a marker of heterogeneity among human naïve CD4+ T cells with important implications for the identification of functionally biased T- cell populations that can be exploited to improve the efficacy of adoptive cell therapies.

New understanding of electrical activity brought by surface potential of cardiomyocytes.

Aiming at the problem encountered in the previous research: during the electrical activity of cardiomyocytes, the influent ions do not seem to be directly derived from the extracellular fluid. We chose to cut in from the colloidal properties of the cells, follow the basic principles of physical chemistry, and establish hypotheses along the derivation of the structural characteristics of cardiomyocytes. Through the surface ion adsorption experiment and patch clamp experiment of living cells, under the condition of sequentially reducing the concentration of Na+ in the extracellular fluid, we observed the exchange and diffusion of adsorbed ions on the cell surface; the changes of inflow INa, ICa-L and action potential; and correlation between results. The results showed that the hypothesis is true. The observed parameter changes were consistent with the fact that during depolarization of cardiomyocytes, the ions of influx were derived from the inference of adsorbed ions on the cell surface; at the same time, it also provided an objective and realistic explanation for the generation of electrocardiogram.