Transition of iPB-1 with low molecular weight crystallized from solutions.

The dimension or entanglement of polymer chains is crucial to chain dynamics, and the polymer chains can be diluted and disentangled in a solution by reducing the interaction with each other. This letter addresses the role of solution concentration in the crystal transition of isotactic polybutene-1 (iPB-1) with low molecular weight crystallized from solution. It turned out that the transition of iPB-1 obtained from the higher concentration of the solution is faster than that obtained from the lower one. In addition, the disparity in the transition between the early stage and later stage for samples prepared from solutions with and without stirring was characterized. DSC and X-ray experiments revealed that initial temperatures for the solution-crystallized iPB-1 to melt and crystallize into form II dominated the transition. The role of entropy in the transition was proposed as a primary factor influencing the iPB-1 transition. Increasing the concentration of the solution or stirring during crystallization increases the supersaturation for iPB-1 to crystalize from the solution and form less stable crystals. The less stable iPB-1 crystals cause the formation of form II at lower temperatures during heating. Therefore, the lower entropy in amorphous regions resulted in an enhanced propensity for the helical conformation with a lower entropy and consequently accelerated the crystal transition.

Form II to form I transition in solution-crystallized isotactic polybutene-1.

Different polymer chains in a solution or melt have different conformations with corresponding entropy at each moment, which would be confined after crystallization. Equilibrium concept-based conformation or conformational entropy depends on chain dynamics, which is related to the effect of energy on conformational changes in polymer chains. Herein, an isotactic polybutene-1 (iPB-1) crystal was crystallized from solution by adding a precipitant at various temperatures. The solution-crystallized iPB-1 crystal was heated to 100 °C to obtain form II at different heat rates and the transition of form II was characterized. It was found that the form II to form I transition was not only related to the precipitation temperature but also to the heating rate of the solution-crystallized iPB-1. Thus, both precipitation temperature and heating rate determine the formation temperature of form II, i.e., form II that crystallized at lower temperature would transform faster. The results indicate that the conformation or conformational entropy of the amorphous region in iPB-1 is important to understand crystal transition.

Melt memory in random ethylene-1-alkene copolymers.

Chain flexibility or stiffness based polymer conformation plays a crucial role in affecting the dynamics and kinetics of polymers, which is related to the hierarchical architecture of chains. A series of random copolymers of ethylene and 1-alkenes including 1-hexene, 1-octene, and 1-dodecene were synthesized with metallocene catalysts. The crystallization behavior and memory effect in random ethylene-1-alkene copolymers with different side groups were investigated via differential scanning calorimetry (DSC) and wide-angle X-ray scattering (WAXS). Rheological tests were performed for understanding their dynamical behavior. The results show that the melting peak and the viscosity decrease but the orthorhombic crystal dimensions increase with co-unit contents increasing in the copolymers. It was found that the scaling relationship between the zero shear viscosity (η0) and molecular weight (Mn) of the copolymers containing ethylene-1-hexene and ethylene-1-octene is 3.6, which is higher than the classical scaling value of 3.4. The memory of crystals in the melt is enhanced with the increase of 1-alkene contents but is independent of the types of 1-alkenes. The enhanced melt memory effect in the copolymers was proposed due to the effect of the 1-alkene based side groups on the dynamics of polymer chains. The present work would be helpful to understand the chain stiffness based polymer dynamics and processing of polyolefins and copolymers prepared with the metallocene catalyst.

Crystallization and melting of unentangled poly(ε-caprolactone) cycles containing pendants.

The Rouse model provides a basic framework to understand the chain dynamics of polymers, which is confirmed to be more suitable for exploring the linear dynamics of unentangled polymers. The crystalline morphology governed by chain dynamics and crystallization kinetics is expected to differ in linear and cyclic polymers. Cyclic poly(ε-caprolactone)s (c-PCLs) containing two bi-anthracenyl group pendants with molecular weights close to the critical molecular weight (Mc) were synthesized to investigate the chain dynamics based crystallization and melting behavior by DSC, POM, and in situ simultaneous small-angle X-ray scattering/wide-angle X-ray scattering (SAXS/WAXS) investigations during heating of the isothermally crystallized samples. Double endothermic peaks were observed in the DSC curves with a low heating rate of c-PCLs without entanglement after isothermal crystallization, especially for c-PCLs with Mc. The structure evolution of the crystalline structures observed from the in situ investigations during the heating and double endothermic peaks in DSC heating curves of the c-PCLs indicate the role of pendants in the chain dynamics, which leads to the reorganization of the metastable structures. Banded spherulites of c-PCL without entanglement were observed for the first time, and the uneven growth of spherulites along the radial direction may be caused by the mismatch between chain dynamics and crystallization kinetics.

Mpemba effect in crystallization of polybutene-1.

The Mpemba effect and its inverse can be understood as a result of nonequilibrium thermodynamics. In polymers, changes of state are generally non-equilibrium processes. However, the Mpemba effect has been rarely reported in the crystallization of polymers. In the melt, polybutene-1 (PB-1) has the lowest critical cooling rate in polyolefins and tends to maintain its original structure and properties with thermal history. A nascent PB-1 sample was prepared by using metallocene catalysis at low temperature, and the crystallization behavior and crystalline structure of the PB-1 were characterized by DSC and WAXS. Experimentally, a clear Mpemba effect is observed not only in the crystallization of the nascent PB-1 melt in form II but also in form I obtained from the nascent PB-1 at low melting temperature. It is proposed that this is due to the differences in the chain conformational entropy in the lattice which influence conformational relaxation times. The entropy and the relaxation time can be predicted using the Adam-Gibbs equations, whereas non-equilibrium thermodynamics is required to describe the crystallization with the Mpemba effect.

Effects of end groups and entanglements on crystallization and melting behaviors of poly(ε-caprolactone).

The topology including end groups, entanglement loops, and tie molecules has a significant impact on the rheological and crystallization behavior and consequently on the functionality of a polymer. Unentangled, weakly entangled, and strongly entangled poly(ε-caprolactone)s (PCLs) with end groups and various molecular weights were synthesized. POM and DSC were used to observe spherulite growth and characterize thermal properties during crystallization and melting. The viscosity and structure of the samples were probed by rheology and X-ray analysis, respectively. The crossover of the scaling relationship of viscosity vs molecular weight demonstrates that the samples cover a wide range of entanglement density, and the bulky end groups cause deviations from the classical scaling laws. In situ simultaneous SAXS/WAXS investigations showed that the crystal structure of PCLs did not change with end groups and heating. The results of POM and DSC imply that the end groups and entanglements affect the crystallization rate and the spherulite morphology. The melting of PCLs containing end groups was found to be a multi-step process involving various nanoscale crystalline structures. The evolution of nanoscale crystalline structures of isothermally crystallized PCLs during heating was analyzed by fitting 1D SAXS profiles, and the continuous structural evolution was found to be a process influenced by end groups and entanglements. The results show that end groups and entanglements affect the chain dynamics and lead to constrained crystallization behavior and the formation of metastable structures, ultimately affecting the structure evolution during melting.

Light-assisted anti-wrinkling on azobenzene-containing polyblend films.

Undesired surface wrinkling is a persistent issue far from being resolved. Here, we report a simple light-assisted strategy to prevent surface wrinkling on azobenzene-containing polyblend films, which is based on the unique photo-responsive behaviors of azobenzene moieties. Upon visible light irradiation, the mechanical strain-induced surface wrinkling of the azo-based polyblend film attached on a pre-strained compliant substrate can be effectively suppressed. The influence of light irradiation conditions and polyblend composition on the wrinkling resistance has been systematically investigated. Notably, empirical scaling laws that can quantify the connection of the critical wrinkling conditions with external and internal factors are derived. This spatiotemporal light-assisted strategy combined with the simple universal blending method would provide a general guideline for the anti-wrinkling purpose in diverse functional material systems/devices.

Metal-Free Oxidative Esterification of Ketones and Potassium Xanthates: Selective Synthesis of α-Ketoesters and Esters.

A novel and efficient oxidative esterification for the selective synthesis of α-ketoesters and esters has been developed under metal-free conditions. In the protocol, various α-ketoesters and esters are available in high yields from commercially available ketones and potassium xanthates. Mechanistic studies have proven that potassium xanthate not only promotes oxidative esterification but also provides an alkoxy moiety for the reaction, which involves the cleavage and reconstruction of C-O bonds.

Bacterial toxins induce non-canonical migracytosis to aggravate acute inflammation.

Migracytosis is a recently described cellular process that generates and releases membrane-bound pomegranate-like organelles called migrasomes. Migracytosis normally occurs during cell migration, participating in various intercellular biological functions. Here, we report a new type of migracytosis induced by small GTPase-targeting toxins. Unlike classic migracytosis, toxin-induced migrasome formation does not rely on cell migration and thus can occur in both mobile and immobile cells. Such non-canonical migracytosis allows the cells to promptly respond to microbial stimuli such as bacterial toxins and effectors and release informative cellular contents in bulk. We demonstrated that C. difficile TcdB3 induces liver endothelial cells and Kupffer cells to produce migrasomes in vivo. Moreover, the migracytosis-defective Tspan9‒/‒ mice show less acute inflammation and lower lethality rate in the toxin challenge assay. Therefore, we propose that the non-canonical migracytosis acts as a new mechanism for mammalian species to sense and exacerbate early immune response upon microbial infections.

PPP1R15A-expressing monocytic MDSCs promote immunosuppressive liver microenvironment in fibrosis-associated hepatocellular carcinoma.

Background & Aims: Recent studies demonstrated the importance of fibrosis in promoting an immunosuppressive liver microenvironment and thereby aggressive hepatocellular carcinoma (HCC) growth and resistance to immune checkpoint blockade (ICB), particularly via monocyte-to-monocytic myeloid-derived suppressor cell (M-MDSC) differentiation triggered by hepatic stellate cells (HSCs). We thus aimed to identify druggable targets in these immunosuppressive myeloid cells for HCC therapy. Methods: M-MDSC signature genes were identified by integrated transcriptomic analysis of a human HSC-monocyte culture system and tumor-surrounding fibrotic livers of patients with HCC. Mechanistic and functional studies were conducted using in vitro-generated and patient-derived M-MDSCs. The therapeutic efficacy of a M-MDSC targeting approach was determined in fibrosis-associated HCC mouse models. Results: We uncovered over-expression of protein phosphatase 1 regulatory subunit 15A (PPP1R15A), a myeloid cell-enriched endoplasmic reticulum stress modulator, in human M-MDSCs that correlated with poor prognosis and ICB non-responsiveness in patients with HCC. Blocking TGF-ß signaling reduced PPP1R15A expression in HSC-induced M-MDSCs, whereas treatment of monocytes by TGF-ß upregulated PPP1R15A, which in turn promoted ARG1 and S100A8/9 expression in M-MDSCs and reduced T-cell proliferation. Consistently, lentiviral-mediated knockdown of Ppp1r15a in vivo significantly reduced ARG1+S100A8/9+ M-MDSCs in fibrotic liver, leading to elevated intratumoral IFN-γ+GZMB+CD8+ T cells and enhanced anti-tumor efficacy of ICB. Notably, pharmacological inhibition of PPP1R15A by Sephin1 reduced the immunosuppressive potential but increased the maturation status of fibrotic HCC patient-derived M-MDSCs. Conclusions: PPP1R15A+ M-MDSC cells are involved in immunosuppression in HCC development and represent a novel potential target for therapies. Impact and implications: Our cross-species analysis has identified PPP1R15A as a therapeutic target governing the anti-T-cell activities of fibrosis-associated M-MDSCs (monocytic myeloid-derived suppressor cells). The results from the preclinical models show that specific inhibition of PPP1R15A can break the immunosuppressive barrier to restrict hepatocellular carcinoma growth and enhance the efficacy of immune checkpoint blockade. PPP1R15A may also function as a prognostic and/or predictive biomarker in patients with hepatocellular carcinoma.

Study of the upregulation of the activity of cytochrome P450 3A isoforms by Astragalus injection and Astragalus granules in rats and in cells.

Astragalus injection (AI) and Astragalus granules (AG) are the two representative clinical preparations from Astragali Radix. In order to investigate the regulation of metabolism, AI and AG were tested for their ability to affect the major enzyme cytochrome P450 3A isoforms in vivo and in vitro. In the study of CYP3A1 enzyme activity, male rats were pretreated with AI and AG. The "cocktail" approach-based LC-MS/MS results showed that AI pretreatment at 0.16, 0.8 and 4 g kg(-1) day(-1) significantly increased the rat liver microsome CYP3A1 activity by 1.62-, 1.68- and 2.00-fold, and AG pretreatment at 32, 160 and 800 mg kg(-1) day(-1) significantly increased the rat CYP3A1 activity by 1.86-, 2.16- and 1.76-fold. The effects of AI and AG on liver microsome CYP3A1 mRNA expression in rats were analyzed using real-time PCR technique. The results showed that AI and AG pretreatments significantly increased the CYP3A1 mRNA expression. The induction of CYP3A4 enzyme activity by AI and AG in vitro was measured using a CYP3A4 luciferase reporter gene assay in transiently transfected human intestinal LS174T cells. Compared to the control group, AI at 62.5-1,000 mg/ml could significantly induce CYP3A4 reporter gene luciferase activity of 1.36- to 1.88-fold for 48-h incubated PXR-transfected LS174T cells, and AG at 62.5-1,000 µg/ml significantly transactivated CYP3A4 reporter gene luciferase activity of 1.36- to 2.05-fold. However, the CYP3A4 reporter gene construct was not significantly transactivated by the AI and AG in CAR-transfected LS174T cells. These CYP3A isoforms upregulation results can help us to use AI and AG rationally in the clinic.

Multi-Task Credible Pseudo-Label Learning for Semi-Supervised Crowd Counting.

As a widely used semi-supervised learning strategy, self-training generates pseudo-labels to alleviate the labor-intensive and time-consuming annotation problems in crowd counting while boosting the model performance with limited labeled data and massive unlabeled data. However, the noise in the pseudo-labels of the density maps greatly hinders the performance of semi-supervised crowd counting. Although auxiliary tasks, e.g., binary segmentation, are utilized to help improve the feature representation learning ability, they are isolated from the main task, i.e., density map regression and the multi-task relationships are totally ignored. To address the above issues, we develop a multi-task credible pseudo-label learning (MTCP) framework for crowd counting, consisting of three multi-task branches, i.e., density regression as the main task, and binary segmentation and confidence prediction as the auxiliary tasks. Multi-task learning is conducted on the labeled data by sharing the same feature extractor for all three tasks and taking multi-task relations into account. To reduce epistemic uncertainty, the labeled data are further expanded, by trimming the labeled data according to the predicted confidence map for low-confidence regions, which can be regarded as an effective data augmentation strategy. For unlabeled data, compared with the existing works that only use the pseudo-labels of binary segmentation, we generate credible pseudo-labels of density maps directly, which can reduce the noise in pseudo-labels and therefore decrease aleatoric uncertainty. Extensive comparisons on four crowd-counting datasets demonstrate the superiority of our proposed model over the competing methods. The code is available at: https://github.com/ljq2000/MTCP.

Myeloid-intrinsic cell cycle-related kinase drives immunosuppression to promote tumorigenesis.

Massive expansion of immature and suppressive myeloid cells is a common feature of malignant solid tumors. Over-expression of cyclin-dependent kinase 20, also known as cell cycle-related kinase (CCRK), in hepatocellular carcinoma (HCC) correlates with reduced patient survival and low immunotherapy responsiveness. Beyond tumor-intrinsic oncogenicity, here we demonstrated that CCRK is upregulated in myeloid cells in tumor-bearing mice and in patients with HCC. Intratumoral injection of Ccrk-knockdown myeloid-derived suppressor cells (MDSCs) increased tumor-infiltrating CD8+T cells and suppressed HCC tumorigenicity. Using an indel mutant transgenic model, we showed that Ccrk inactivation in myeloid cells conferred a mature phenotype with elevated IL-12 production, driving Th1 responses and CD8+T cell cytotoxicity to reduce orthotopic tumor growth and prolong survival. Mechanistically, CCRK activates STAT3/E4BP4 signaling in MDSCs to acquire immunosuppressive activity through transcriptional IL-10 induction and IL-12 suppression. Taken together, our findings unravel mechanistic insights into MDSC-mediated immunosuppression and offer a therapeutic kinase-target for cancer immunotherapy.

Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver.

Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development. Moreover, suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin (mTOR) inhibitor vistusertib preceded tumor regression, which was abolished by NKT inactivation but not CD8+ T cell depletion. Mechanistically, sterol regulatory element-binding protein 2 (SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells, which were supported by findings in people with obesity, NAFLD and NAFLD-HCC. This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment, providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.

Cell cycle-related kinase reprograms the liver immune microenvironment to promote cancer metastasis.

The liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types. Although a role for cancer cell invasion programs has been well characterized, whether and how liver-intrinsic factors drive metastatic spread is incompletely understood. Here, we show that aberrantly activated hepatocyte-intrinsic cell cycle-related kinase (CCRK) signaling in chronic liver diseases is critical for cancer metastasis by reprogramming an immunosuppressive microenvironment. Using an inducible liver-specific transgenic model, we found that CCRK overexpression dramatically increased both B16F10 melanoma and MC38 colorectal cancer (CRC) metastasis to the liver, which was highly infiltrated by polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) and lacking natural killer T (NKT) cells. Depletion of PMN-MDSCs in CCRK transgenic mice restored NKT cell levels and their interferon gamma production and reduced liver metastasis to 2.7% and 0.7% (metastatic tumor weights) in the melanoma and CRC models, respectively. Mechanistically, CCRK activated nuclear factor-kappa B (NF-κB) signaling to increase the PMN-MDSC-trafficking chemokine C-X-C motif ligand 1 (CXCL1), which was positively correlated with liver-infiltrating PMN-MDSC levels in CCRK transgenic mice. Accordingly, CRC liver metastasis patients exhibited hyperactivation of hepatic CCRK/NF-κB/CXCL1 signaling, which was associated with accumulation of PMN-MDSCs and paucity of NKT cells compared to healthy liver transplantation donors. In summary, this study demonstrates that immunosuppressive reprogramming by hepatic CCRK signaling undermines antimetastatic immunosurveillance. Our findings offer new mechanistic insights and therapeutic targets for liver metastasis intervention.

Elevated Levels of Oxidative Nucleic Acid Modification Markers in Urine From Gastric Cancer Patients: Quantitative Analysis by Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry.

Oxidative nucleic acid modifications have attracted increasing attention in recent years since they have been found to be related to a number of diseases including cancer. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG) are the typical markers of oxidative modification of DNA and RNA, respectively, and they are emerging biomarkers for the early detection of diseases. Urine is a favored biofluid for biomarker discovery due to its noninvasiveness to patients. Accurate quantification of these oxidative nucleic acid modifications still has challenges because their amounts in urine are very low and the interferences in urine samples are complicated. Herein, we developed and validated an accurate and robust solid-phase extraction (SPE) coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous quantification of these oxidative nucleic acid modifications in human urine. Stable isotope dilution strategy was utilized and the method shows good precision on intraday and interday measurements. Meanwhile, recovery was satisfactory by utilizing the Oasis hydrophilic-lipophilic balance (HLB) cartridge for sample pretreatment at three spiked levels. We successfully quantified urinary 8-OHdG and 8-OHG from 60 gastric cancer patients and 70 healthy controls by using this method. The measured contents of 8-OHdG and 8-OHG in urine from gastric cancer patients are both increased, compared with those in urine from healthy controls, indicating these oxidative nucleic acid modifications could act as potential non-invasive markers for early diagnosis of gastric cancer. Moreover, the present study will stimulate investigations of the effects of oxidative stress and nucleic acid modifications on the initiation and progression of gastric cancer.

Quantitative determination of the spring entropy effect and its indication of the conformational change of polymer coils with varying concentration in aqueous poly(N-isopropylamide) solutions.

The lower critical solution temperature (LCST) phase separation behaviors of thermosensitive poly(N-isopropylacrylamide) (PNIPAM) aqueous solutions were investigated by power-compensation differential scanning calorimetry (DSC). The entropic effect and hence the change of swelling state of PNIPAM polymer coils in homogeneous concentrated aqueous solutions with varied solution composition was elucidated by the isothermal enthalpy demixing recovery behaviors in distinct concentration regions.

Effect of preoperative transcatheter arterial chemoembolization on proliferation of hepatocellular carcinoma cells.

AIM: To evaluate the effect of preoperative transcatheter arterial chemoembolization (TACE) on proliferation of hepatocellular carcinoma (HCC) cells. METHODS: A total of 136 patients with HCC underwent liver resection. Of 136 patients, 79 patients received 1 to 5 courses of TACE prior to liver resection (TACE group), who were further subdivided into four groups: Group A (n = 11) who received 1 to 4 courses of chemotherapy alone; Group B (n = 33) who received 1 to 5 courses of chemotherapy combined with iodized oil; Group C (n = 23) who received 1 to 3 courses of chemotherapy combined with iodized oil and gelatin sponge; and Group D (n = 12) who received 1 to 3 courses of chemotherapy combined with iodized oil, ethanol and gelatin sponge. The other 57 patients only received liver resection (non-TACE group). The expressions of Ki-67 and proliferating cell nuclear antigen (PCNA) protein were detected in the liver cancer tissues by immunohistochemical method. RESULTS: The Ki-67 protein expression was significantly lower in Groups C and D as compared with non-TACE group (31.35% +/- 10.85% vs 44.43% +/- 20.70%, 30.93% +/- 18.10% vs 44.43% +/- 20.70%, respectively, P < 0.05). The PCNA protein expression was significantly lower in Groups C and D as compared with non-TACE group (49.61% +/- 15.11% vs 62.92% +/- 17.21%, 41.16% +/- 11.83% vs 62.92% +/- 17.21%, respectively, P < 0.05). The Ki-67 protein expression was significantly higher in Group A as compared with non-TACE group (55.44% +/- 13.72% vs 44.43% +/- 20.70%, P < 0.05). The PCNA protein expression was significantly higher in Groups A and B as compared with non-TACE group (72.22% +/- 8.71% vs 62.92% +/- 17.21%, 69.91% +/- 13.38% vs 62.92% +/- 17.21%, respectively, P < 0.05). CONCLUSION: Preoperative multi-material TACE suppresses the proliferation of HCC cells, while a single material embolization and chemotherapy alone enhance the proliferation of HCC cells.

Disrupted Brain Network in Children with Autism Spectrum Disorder.

Alterations in brain connectivity have been extensively reported in autism spectrum disorder (ASD), while their effects on the topology of brain network are still unclear. This study investigated whether and how the brain networks in children with ASD were abnormally organized with resting state EEG. Temporal synchronization analysis was first applied to capture the aberrant brain connectivity. Then brain network topology was characterized by three graph analysis methods including the commonly-used weighted and binary graph, as well as minimum spanning tree (MST). Whole brain connectivity in ASD group was found to be significantly reduced in theta and alpha band compared to typically development children (TD). Weighted graph found significantly decreased path length together with marginally significantly decreased clustering coefficient in ASD in alpha band, indicating a loss of small-world architecture to a random network. Such abnormal network topology was also demonstrated in the binary graph. In MST analysis, children with ASD showed a significant lower leaf fractions with a decrease trend of tree hierarchy in the alpha band, suggesting a shift towards line-like decentralized organization in ASD. The altered brain network may offer an insight into the underlying pathology of ASD and possibly serve as a biomarker that may aid in diagnosis of ASD.

Effects of iron-chelators on ion-channels and HIF-1alpha in the carotid body.

Acute hypoxia instantaneously increases the chemosensory discharge from the carotid body, increasing ventilation mostly by inhibiting the oxygen sensitive ion channels and exciting the mitochondrial functions in the glomus cells. On the other hand, Fe2+-chelation mimics hypoxia by inhibiting the prolyl hydroxylases and the degradation of HIF-1alpha in non-excitable cells. Whether Fe2+-chelation can inhibit the ion channels giving rise to the sensory responses in excitable cells was the question. We characterized the responses to Fe2+-chelators on excitable glomus cells of the rat, and found that they instantaneously blocked the ion-channels, exciting the chemosensory discharge, and later causing a gradual accumulation of HIF-1alpha. Although initiated by the same stimuli, the two effects (on ion channels and cytosolic HIF-1alpha) possibly occurred by two different mechanisms.