Role of HCN channels in the functions of basal ganglia and Parkinson's disease.

Parkinson's disease (PD) is a motor disorder resulting from dopaminergic neuron degeneration in the substantia nigra caused by age, genetics, and environment. The disease severely impacts a patient's quality of life and can even be life-threatening. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is a member of the HCN1-4 gene family and is widely expressed in basal ganglia nuclei. The hyperpolarization-activated current mediated by the HCN channel has a distinct impact on neuronal excitability and rhythmic activity associated with PD pathogenesis, as it affects the firing activity, including both firing rate and firing pattern, of neurons in the basal ganglia nuclei. This review aims to comprehensively understand the characteristics of HCN channels by summarizing their regulatory role in neuronal firing activity of the basal ganglia nuclei. Furthermore, the distribution and characteristics of HCN channels in each nucleus of the basal ganglia group and their effect on PD symptoms through modulating neuronal electrical activity are discussed. Since the roles of the substantia nigra pars compacta and reticulata, as well as globus pallidus externus and internus, are distinct in the basal ganglia circuit, they are individually described. Lastly, this investigation briefly highlights that the HCN channel expressed on microglia plays a role in the pathological process of PD by affecting the neuroinflammatory response.

Novel Effective Photocatalytic Self-Cleaning Coatings: TiO2-Polyfluoroalkoxy Coatings Prepared by Suspension Plasma Spraying.

Photocatalytic coatings can degrade volatile organic compounds into non-toxic products, which has drawn the attention of scholars around the world. However, the pollution of dust on the coating adversely affects the photocatalytic efficiency and service life of the coating. Here, a series of TiO2-polyfluoroalkoxy (PFA) coatings with different contents of PFA were fabricated by suspension plasma spraying technology. The results demonstrate that the hybrid coatings contain a large number of circular and ellipsoidal nanoparticles and a porous micron-nano structure due to the inclusion of PFA. According to the optimized thermal spraying process parameters, TiO2 nanoparticles were partially melted to retain most of the anatase phases, whereas PFA did not undergo significant carbonization. As compared to the TiO2 coating, the static contact angle of the composite coating doped with 25 wt.% PFA increased from 28.2° to 134.1°. In addition, PFA strongly adsorbs methylene blue, resulting in a greater involvement of methylene blue molecules in the catalyst, where the catalytic rate of hybrid coatings is up to 95%. The presented nanocomposite coatings possess excellent photocatalytic and self-cleaning properties and are expected to find wider practical applications in the field of photocatalysis.

Ameliorating parkinsonian motor dysfunction by targeting histamine receptors in entopeduncular nucleus-thalamus circuitry.

In Parkinson's disease (PD), reduced dopamine levels in the basal ganglia have been associated with altered neuronal firing and motor dysfunction. It remains unclear whether the altered firing rate or pattern of basal ganglia neurons leads to parkinsonism-associated motor dysfunction. In the present study, we show that increased histaminergic innervation of the entopeduncular nucleus (EPN) in the mouse model of PD leads to activation of EPN parvalbumin (PV) neurons projecting to the thalamic motor nucleus via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels coupled to postsynaptic H2R. Simultaneously, this effect is negatively regulated by presynaptic H3R activation in subthalamic nucleus (STN) glutamatergic neurons projecting to the EPN. Notably, the activation of both types of receptors ameliorates parkinsonism-associated motor dysfunction. Pharmacological activation of H2R or genetic upregulation of HCN2 in EPNPV neurons, which reduce neuronal burst firing, ameliorates parkinsonism-associated motor dysfunction independent of changes in the neuronal firing rate. In addition, optogenetic inhibition of EPNPV neurons and pharmacological activation or genetic upregulation of H3R in EPN-projecting STNGlu neurons ameliorate parkinsonism-associated motor dysfunction by reducing the firing rate rather than altering the firing pattern of EPNPV neurons. Thus, although a reduced firing rate and more regular firing pattern of EPNPV neurons correlate with amelioration in parkinsonism-associated motor dysfunction, the firing pattern appears to be more critical in this context. These results also confirm that targeting H2R and its downstream HCN2 channel in EPNPV neurons and H3R in EPN-projecting STNGlu neurons may represent potential therapeutic strategies for the clinical treatment of parkinsonism-associated motor dysfunction.

Histamine bidirectionally regulates the intrinsic excitability of parvalbumin-positive neurons in the lateral globus pallidus and promotes motor behaviour.

BACKGROUND AND PURPOSE: Parvalbumin (PV)-positive neurons are a type of neuron in the lateral globus pallidus (LGP) which plays an important role in motor control. The present study investigated the effect of histamine on LGPPV neurons and motor behaviour. EXPERIMENTAL APPROACH: Histamine levels in LGP as well as its histaminergic innervation were determined through brain stimulation, microdialysis, anterograde tracing and immunostaining. Mechanisms of histamine action were detected by immunostaining, single-cell qPCR, whole-cell patch-clamp recording, optogenetic stimulation and CRISPR/Cas9 gene-editing techniques. The effect of histamine on motor behaviour was detected by animal behavioural tests. KEY RESULTS: A direct histaminergic innervation in LGP from the tuberomammillary nucleus (TMN) and a histamine-induced increase in the intrinsic excitability of LGPPV neurons were determined by pharmacological blockade or by genetic knockout of the histamine H1 receptor (H1 R)-coupled TWIK-related potassium channel-1 (TREK-1) and the small-conductance calcium-activated potassium channel (SK3), as well as by activation or overexpression of the histamine H2 receptor (H2 R)-coupled hyperpolarization-activated cyclic nucleotide-gated channel (HCN2). Histamine negatively regulated the STN → LGPGlu transmission in LGPPV neurons via the histamine H3 receptor (H3 R), whereas blockage or knockout of H3 R increased the intrinsic excitability of LGPPV neurons. CONCLUSIONS AND IMPLICATIONS: Our results indicated that the endogenous histaminergic innervation in the LGP can bidirectionally promote motor control by increasing the intrinsic excitability of LGPPV neurons through postsynaptic H1 R and H2 R, albeit its action was negatively regulated by the presynaptic H3 R, thereby suggesting possible role of histamine in motor deficits manifested in Parkinson's disease (PD).

Receptor and Ionic Mechanism of Histamine on Mouse Dorsolateral Striatal Neurons.

The dorsolateral striatum (DLS) is the critical neural substrate that plays a role in motor control and motor learning. Our past study revealed a direct histaminergic projection from the tuberomammillary nucleus (TMN) of the hypothalamus to the rat striatum. However, the afferent of histaminergic fibers in the mouse DLS, the effect of histamine on DLS neurons, and the underlying receptor and ionic mechanisms remain unclear. Here, we demonstrated a direct histaminergic innervation from the TMN in the mouse DLS, and histamine excited both the direct-pathway spiny projection neurons (d-SPNs) and the indirect-pathway spiny projection neurons (i-SPNs) of DLS via activation of postsynaptic H1R and H2R, albeit activation of presynaptic H3R suppressed neuronal activity by inhibiting glutamatergic synaptic transmission on d-SPNs and i-SPNs in DLS. Moreover, sodium-calcium exchanger 3 (NCX3), potassium-leak channels linked to H1R, and hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) coupled to H2R co-mediated the excitatory effect induced by histamine on d-SPNs and i-SPNs in DLS. These results demonstrated the pre- and postsynaptic receptors and their downstream multiple ionic mechanisms underlying the inhibitory and excitatory effects of histamine on d-SPNs and i-SPNs in DLS, suggesting a potential modulatory effect of the central histaminergic system on the DLS as well as its related motor control and motor learning.

Insights into the Mechanisms of Reuterin against Staphylococcus aureus Based on Membrane Damage and Untargeted Metabolomics.

Reuterin is a dynamic small-molecule complex produced through glycerol fermentation by Limosilactobacillus reuteri and has potential as a food biopreservative. Despite its broad-spectrum antimicrobial activity, the underlying mechanism of action of reuterin is still elusive. The present paper aimed to explore the antibacterial mechanism of reuterin and its effects on membrane damage and the intracellular metabolome of S. aureus. Our results showed that reuterin has a minimum inhibitory concentration of 18.25 mM against S. aureus, based on the 3-hydroxypropionaldehyde level. Key indicators such as extracellular electrical conductivity, membrane potential and permeability were significantly increased, while intracellular pH, ATP and DNA were markedly decreased, implying that reuterin causes a disruption to the structure of the cell membrane. The morphological damage to the cells was confirmed by scanning electron microscopy. Subsequent metabolomic analysis identified significant alterations in metabolites primarily involved in lipid, amino acid, carbohydrate metabolism and phosphotransferase system, which is crucial for cell membrane regulation and energy supply. Consequently, these findings indicated that the antibacterial mechanism of reuterin initially targets lipid and amino acid metabolism, leading to cell membrane damage, which subsequently results in energy metabolism disorder and, ultimately, cell death. This paper offers innovative perspectives on the antibacterial mechanism of reuterin, contributing to its potential application as a food preservative.

A Conductive Bamboo Fabric with Controllable Resistance for Tailoring Wearable Sensors.

Force-sensitive textile sensors are becoming a research hotspot as a part of wearable devices. The core research topic is the method to obtain the sensing property, which decides the sensitivity and service performance of the sensors. Here, we introduce a new sensing mechanism based on a statistical change of contact resistance that exhibits an exponential decay upon strain or pressure, where a novel conductive bamboo fabric is prepared and the dependence of electric conductivity on the fabric structure is discovered. The fabric surface resistivity (ρs) is anisotropic with respect to the measuring directions and the warp, weft, and linear densities. The surface resistance (Rs) decreases rapidly under pulling force, especially in diagonal directions, making it available in designing strain sensors. The volume resistivity (ρv) decreases with increasing weft and linear densities, too. The vertical resistance (Rv) decays exponentially under pressure, and the rule is retained even if the fabric is coated with a polymer, leading to diverse possible pressure sensors with a good service performance (e.g., waterproof). Finally, the conductive fabric could be facilely tailored to various wearable sensors with a fast response time, e.g., sensing finger sleeves and sensing insole, which could be used to operate the manipulator's fingers or to monitor human walking gestures, respectively.

Effect of visual endotracheal tube combined with bronchial occluder on pulmonary ventilation and arterial blood gas in patients undergoing thoracic surgery.

Background: To investigate the effect of visual endotracheal tube combined with bronchial occluder on pulmonary ventilation and arterial blood gas in patients undergoing thoracic surgery. Methods: Ninety patients who underwent thoracic surgery under anesthesia and required pulmonary ventilation at our hospital from May 2020 to December 2021 were collected. The patients were divided into three groups according to different intubation methods: visual double-lumen endotracheal tube group (VDLT group), bronchial occluder group (BO group), and VDLT + BO group. Clinical data and laboratory test data were collected from the three groups. Additionally, the three groups were compared in terms of peak airway pressure, time to correct positioning, pulmonary ventilation time, hemodynamics before and after intubation, intubation success rate, and postoperative recovery. Results: The VDLT + BO group was superior to the BO group or VDLT group in airway peak pressure, time to correct positioning, pulmonary ventilation time, intubation success rate, and hemodynamics after intubation (P < 0.05). In the comparison of postoperative recovery, the postoperative pain score, white blood cell level, incidence rate of pneumonia, hospital stay and hospitalization costs in the VDLT + BO group were significantly lower than those in the BO group or VDLT group (P < 0.05). Conclusion: The visual endotracheal tube combined with bronchial occluder is effective in pulmonary ventilation during thoracic surgery under anesthesia, and can improve arterial blood gas in patients.

A pH-response chemotherapy synergistic photothermal therapy for tumor suppression and bone regeneration by mussel-inspired Mg implant.

Primary malignant bone tumors can be life-threatening. Surgical resection of tumor plus chemotherapy is the standard clinical treatment. However, postoperative recovery is hindered due to tumor recurrence caused by residual tumor cells and bone defect caused by resection of tumor tissue. Herein, a multifunctional mussel-inspired film was fabricated on Mg alloy, that is, an inner hydrothermal-treated layer, a middle layer of polydopamine, and an outer layer of doxorubicin. The modified Mg alloy showed excellent photothermal effect and thermal/pH-controlled release of doxorubicin. The synergistic effect of chemotherapy and photothermal therapy enabled the modified Mg alloy to kill bone tumor in vitro and inhibit tumor growth in nude mice. Moreover, because of the controlled release of Mg ions and biocompatibility of polydopamine, the modified Mg alloy supported extracellular matrix mineralization, alkaline phosphatase activity, and bone-related gene expression in C3H10T1/2. Bone implantation model in rats verified that the modified Mg showed excellent osteointegration. These findings prove that the use of mussel-inspired multifunction film on Mg alloy offers a promising strategy for the therapy of primary malignant bone tumor.

A phase I/II clinical trial on the efficacy and safety of NKT cells combined with gefitinib for advanced EGFR-mutated non-small-cell lung cancer.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, have achieved good efficacy in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients, but eventual drug resistance is inevitable. Thus, new TKI-based combination therapies should be urgently explored to extend the overall survival time of these patients. CD8 + CD56+ natural killer T (NKT) cells are a natural and unique subset of lymphocytes in humans that present characteristics of T and NK cells and exert cytotoxicity on tumour cells in a granzyme B-dependent manner. The aim of this trial was to explore the efficacy and safety of CD8 + CD56+ NKT cell immunotherapy combined with gefitinib in patients with advanced EGFR-mutated NSCLC. METHODS: The study was designed as a prospective, randomized, controlled, open-label, phase I/II trial that includes 30 patients with EGFR mutation-positive stage III/IV NSCLC. All patients will be randomized in blocks at a 1:1 ratio and treated with gefitinib 250 mg/day monotherapy or combination therapy with allogeneic CD8 + CD56+ NKT cell infusions twice per month for 12 cycles or until disease progression occurs. The effectiveness of this treatment will be evaluated based on by progression-free survival (PFS), the time to progression (TTP), overall response rate (ORR), disease control rate (DCR) and overall survival (OS). The safety of the trail is being assessed based on adverse events (AEs). Recruitment and data collection, which started in December 2017, are ongoing. DISCUSSION: Although immunotherapy, including programmed death-1/programmed death-1 ligand (PD-1/PD-L1) immunotherapy, has been used for NSCLC treatment with or without EGFR-TKIs, its clear efficacy still has not been shown. Assessing the safety and therapeutic potential of allogeneic CD8 + CD56+ NKT killer cells in combination with EGFR-TKIs in NSCLC will be of great interest. TRIAL REGISTRATION: This trial (Phase I/II Trails of NKT Cell in Combination With Gefitinib For Non Small Cell Lung Cancer) was registered on 21 November 2017 with www.chictr.org.cn , ChiCTR-IIR-17013471 .

The Efficacy and Safety of Paravertebral Block Combined with Parecoxib During Video-Assisted Thoracic Surgery: A Randomized Controlled Trial.

BACKGROUND: Although video-assisted thoracoscopic surgery (VATS) is increasingly used, the optimal analgesia strategy is still unknown. We explore the efficacy and safety of preemptive ultrasound-guided paravertebral block (PVB) combined with parecoxib during VATS. METHODS: Seventy-four patients were divided into two groups. PVBs were performed before anesthesia induction under real-time ultrasound guidance. Visual analog scale (VAS) score with coughing at 48 h after surgery, postoperative sufentanil consumption and level of sedation (LOS) at 1, 4, 8, 12, 24, and 48 h postoperatively, intraoperative hemodynamics, satisfaction scores of patients and surgeons, remedial measures, time to chest tube removed and mobilization, adverse effects and hospital stay length were recorded. We also recorded inflammatory markers, respiratory function and the prevalence of chronic pain after surgery. RESULTS: VAS scores at rest and with coughing during the first 24 h after surgery were significantly lower in the P group (P<0.05). Consumption of sevoflurane, remifentanil, and dexmedetomidine was all significantly reduced in the P group (P<0.05). The consumption of sufentanil within 48 h after surgery, time to first dose and total dose of rescue ketorolac was significantly lower in the P group (P<0.05). The FEV1/FVC ratio was significantly higher in the P group at 1 and 3 d after surgery (P<0.05). Times to chest tube removal and mobilization were significantly shorter in the P group (P<0.05). Compared with the C group, the level of both ACTH and cortisol was significantly reduced in the P group at 1 and 3 d after surgery (P<0.05). CONCLUSION: PVB combined with parecoxib was associated with better pain relief, decreased sufentanil and ketorolac consumption, less hemodynamic instability, and a lower surgery-related stress response. However, the incidences of chronic pain 3 and 6 months after surgery and the risk of complication except urinary retention were not significantly different between groups.

Elementary photoelectronic processes at a porphyrin dye/single-walled TiO2 nanotube hetero-interface in dye-sensitized solar cells: a first-principles study.

A unique one-dimensional (1D) sandwich single-walled TiO2 nanotube (STNT) is proposed as a photoanode nanomaterial with perfect morphology and large specific surface area. We have thoroughly examined the elementary photoelectronic processes occurring at the porphyrin dye/STNT hetero-interface in dye-sensitized solar cells (DSSCs) by theoretical simulation. It is desirable to investigate the interfacial photoelectronic processes to elucidate the electron transfer and transport mechanism in 1D STNT-based DSSCs. We have found that the photoexcitation and interfacial charge separation mechanism can be described as follows. A ground-state electron of the dye molecule (localized around the electron donor) is first promoted to the excited state (distributed electron donor), and then undergoes ultrafast injection into the conduction band of the STNT, leaving a hole around the oxidized dye. Significantly, the injected electron in the conduction band is transported along the STNT by means of Ti 3d (x2-y2) orbitals, offering a unidirectional electron pathway toward the electrode for massive collection without the observation of trap states. Our study not only provides theoretical guidelines for the modification of TiO2 nanotubes as a photoanode material, but also opens a new perspective for the development of a novel class of TiO2 nanotubes with high power-generation efficiency.

Magnetic Fe3O4-graphene composites as targeted drug nanocarriers for pH-activated release.

A novel nanocarrier of magnetic Fe(3)O(4)-graphene nanocomposites (MGNs) was proposed as an effective drug delivery system for cancer treatment. The nanocarrier was synthesized by covalently attaching modified Fe(3)O(4) nanoparticles onto water-soluble graphene sheets via the formation of an amide bond with the aid of 1-ethyl-3-(3-dimethyaminopropyl) carbodiimide. The obtained MGNs exhibited excellent dispersibility and stability in aqueous solution and they also exhibited superparamagnetic properties with a saturation magnetization of 23.096 emu g(-1). An efficient loading of 5-fluorouracil (5-FU) on MGNs as high as 0.35 mg mg(-1) was obtained. Furthermore, the in vitro drug release of 5-FU was examined in pH 6.9 and pH 4.0 buffers at 37 °C, and showed strong pH dependence. Transmission electron microscope observations revealed that MGNs can be internalized efficiently by HepG2 cells. More importantly, the cytotoxicity evaluation shows that the resulting MGNs exhibit excellent biocompatibility. The as-prepared nanocarrier system combined the advantages of the superparamagnetic iron oxide nanoparticles and water-soluble graphene sheets, which will find many potential applications in biomedicine and biomaterials.

The preparation and drug delivery of a graphene-carbon nanotube-Fe3O4 nanoparticle hybrid.

We report a green and facile procedure of synthesizing a graphene nanosheet-carbon nanotube-iron oxide nanoparticle hybrid (GN-CNT-Fe3O4) as a promising platform for the loading and delivery of anticancer drugs. The obtained GN-CNT-Fe3O4 hybrid exhibited superparamagnetic properties with the saturation magnetization of 19.824 emu g-1. This hybrid nanostructure possesses a superior capability of binding the anticancer drug 5-fluorouracil (5-FU) with a high loading capacity of up to 0.27 mg mg-1 with a 5-FU concentration of 0.5 mg mL-1, and also possesses a pH-activated release profile. Moreover, cellular uptake studies show that the resulting GN-CNT-Fe3O4 hybrid can be internalized efficiently by HepG2 cells. In vitro cytotoxicity tests suggest that the obtained GN-CNT-Fe3O4 hybrid is nontoxic for Chang liver cells, even at the high concentration of 80 µg mL-1, however, the 5-FU-loaded GN-CNT-Fe3O4 hybrid showed significant cytotoxic effects in HepG2 cells. The results show that this novel 3D hybrid is a promising candidate for anti-cancer drug delivery systems.

Compensation: a contemporary regulatory machinery in cardiovascular diseases?

Both clinical and experimental findings at the molecular, cellular, tissue, organ and systematic levels have depicted the presence of a contemporary regulatory machinery namely compensation in various forms of cardiovascular diseases. Compensation is believed to be present and regulated within the scope of a biological entity and represents the initiation of dyshomeostasis. Compensation can be identified in multiple categories and organs in cardiovascular diseases at multiple levels. The capacity to reduce the unfavorable pathological compensation may be a criterion to evaluate the therapeutic effectiveness for cardiovascular diseases. This mini-review tries to take compensation into consideration in the understanding of onset and progression of cardiovascular diseases in particular, and thus, better or optimal therapeutic approaches may be achieved for the prevention and management of cardiovascular diseases.

Genetic analysis of the P1 region of human enterovirus 71 strains and expression of the 55 F strainVP1 protein.

Enterovirus 71 (EV71) is a member of the Entero-virus genus of the Picornaviridae family and is the major cause of Hand, foot, and mouth disease (HFMD) in children. Different strains from Gansu were cloned and the P1 protein was sequenced and analysed. Results indicate that there are three kinds of EV71 infections prevalent in Gansu. The VP1 protein from one of these strains, 55F, was expressed. The recombinant protein was expressed with high level and reacted specifically with the EV71 patient antibody, the recombinant protein was also applied to raise antiserum in rabbits and after the fourth injection a high titer of antiserum was detected by ELISA assay. These data are useful for further clarification of prevalent EV71 strains in the north of China at the molecular level and provide a basis for EV71 diagnosis.

Influence of gestational overfeeding on cardiac morphometry and hypertrophic protein markers in fetal sheep.

Intrauterine overnutrition is associated with development of cardiovascular disease in adulthood although the underlying mechanism has not been precisely elucidated. This study evaluated the effects of maternal overnutrition on fetal cardiac morphometry and hypertrophy-related mRNA/protein expression. Multiparous ewes were fed either 150% of National Research Council (NRC) nutrient requirements (overfed group) or 100% of NRC requirements (control group) from 60 days before mating to Day 75 (D75) of gestation, when ewes were euthanized. Cardiac morphometry, histology and expression of Akt, forkhead-3a (Foxo3a), glycogen synthase kinase-3ß (GSK3ß), mammalian target of rapamycin (mTOR), NFATc3 and GATA4, atrial natriuretic factor (ANF), calcineurin A and caspase-8 were examined. Crown rump length, left and right ventricular free wall weights and left ventricular wall thickness were increased in D75 overnourished fetuses. Hematoxylin and eosin staining revealed irregular myofiber orientation and increased interstitial space in heart tissues from overfed group. Masson's trichrome staining displayed myofiber hypertrophy and fascicular disarray in heart tissues from overfed group. Overfeeding significantly enhanced Foxo3a phosphorylation in both ventricles, while protein expression of Akt, Foxo3a, GSK3ß and caspase-8 as well as phosphorylated Akt and GSK3ß in either ventricle was unaffected. Overfeeding increased left ventricular mTOR, NFATc3 (both total and phosphorylated) and calcineurin A. GATA4, pGATA4 and ANF expression were unchanged in both ventricles. Collectively, our data suggested that overfeeding during early to mid gestation (D75) leads to morphometric changes without overt pathology which may be related to elevated expression of mTOR, NFATc3, calcineurin A and phosphorylation of Foxo3a, mTOR and NFATc3.

Homeostasis and compensatory homeostasis: bridging Western medicine and traditional chinese medicine.

Compensation is a self-protective mechanism in diseases, which may lead to a unique form of homeostasis deviates from that in physiological conditions. The kind of compensatory homeostasis can be embodied as various degrees accompanying disease progression (denoted as compensatory degree). Compensatory homeostasis provides a window for the transition from disease to healthy state. The causes of compensatory homeostasis themselves may be identified as targets for effective measures to eliminate compensation. Compensatory homeostasis embodies significantly mostly in the developing process of chronic diseases, which may help to explain in theory why intensive therapeutic strategies led to unexpected outcome in clinical practice. In addition, a large body of clinical evidence has valued traditional Chinese medicine (TCM), which is based on shifting compensatory homeostasis to the overall human body homeostasis, complementary to Western medicine in the management of chronic disease. In this review, we will briefly summarize the concept of compensation and attempt to bridge Western and traditional Chinese medicine through homeostasis and compensatory homeostasis based on an ample of evidence obtained from both disciplines.

AMP-activated protein kinase deficiency exacerbates aging-induced myocardial contractile dysfunction.

Aging is associated with myocardial dysfunction although the underlying mechanism is unclear. AMPK, a key cellular fuel sensor for energy metabolism, is compromised with aging. This study examined the role of AMPK deficiency in aging-associated myocardial dysfunction. Young or old wild-type (WT) and transgenic mice with overexpression of a mutant AMPK alpha(2) subunit (kinase dead, KD) were used. AMPK alpha isoform activity, myocardial function and morphology were examined. DCF and JC-1 fluorescence probes were employed to quantify reactive oxygen species (ROS) and mitochondrial membrane potential (DeltaPsim), respectively. KD mice displayed significantly reduced alpha(2) but not alpha(1) AMPK isoform activity at both ages with a greater effect at old age. Aging itself decreased alpha(1) isoform activity. Cardiomyocyte contractile function, intracellular Ca(2+) handling, and SERCA2a levels were compromised with aging, the effects of which were exacerbated by AMPK deficiency. H&E staining revealed cardiomyocyte hypertrophy with aging, which was more pronounced in KD mice. TEM micrographs displayed severe disruption of mitochondrial ultrastructure characterized by swollen, irregular shape and disrupted cristae in aged KD compared with WT mice. Aging enhanced ROS production and reduced DeltaPsim, the effects of which were accentuated by AMPK deficiency. Immunoblotting data depicted unchanged Akt phosphorylation and a significant decrease in mitochondrial biogenesis cofactor PGC-1alpha in aged groups. AMPK deficiency but not aging decreased the phosphorylation of ACC and eNOS. Expression of membrane Glut4 and HSP90 was decreased in aged KD mice. Moreover, treatment of the AMPK activator metformin attenuated aging-induced cardiomyocyte contractile defects. Collectively, our data suggest a role for AMPK deficiency in aging-induced cardiac dysfunction possibly through disrupted mitochondrial function and ROS production.

[Characteristics and loads of key sources of pollutions discharged into Beishi River, Changzhou City].

Choosing the Beishi river, Changzhou City as the study area, the sewage generation, pollutants characteristics and sewage discharge in catchment area of Beishi river were conducted, detailed investigated and monitored. After using pollution coefficients, the yearly loads of all sources of pollutions were calculated to determine the highest sewage. The results showed that: except pH, the high concentration of SS, COD, BOD5, ammonia nitrogen, TN and TP discharged from MSW collecting houses, MSW transfer stations, public toilets and dining in Changzhou city far exceeded the "Integrated Wastewater Discharge Standard" (GB 8978-1996) and "Effluent Discharged into the City Sewer Water Quality Standards" (CJ 3082-1999). Among which: the highest concentration of COD discharged from MSW transfer stations was up to 51 700 mg/L, while the ammonia nitrogen and TN were as high as 1 616 mg/L and 2 044 mg/L in the toilet wastewater. In addition to this, the ratio of wastewater discharged directly into the river through storm water pipe network was higher from MSW houses, MSW transfer stations, public toilets, dining and other waste in Changzhou city. The 125.2 t/a of COD and 40.53 t/a of BOD5 were the two highest concentrations of various sources of pollution. The highest annual polluting loads discharged into Beishi river is dining, followed by the sanitation facilities. Therefore, cutting pollution control of food and sanitation facilities along the river is particularly urgent.