Piezo1-Mediated Neurogenic Inflammatory Cascade Exacerbates Ventricular Remodeling After Myocardial Infarction.

BACKGROUND: Heart failure is associated with a high rate of mortality and morbidity, and ventricular remodeling invariably precedes heart failure. Ventricular remodeling is fundamentally driven by mechanotransduction that is regulated by both the nervous system and the immune system. However, it remains unknown which key molecular factors govern the neuro/immune/cardio axis that underlies mechanotransduction during ventricular remodeling. Here, we investigated whether the mechanosensitive Piezo cation channel-mediated neurogenic inflammatory cascade underlies ventricular remodeling-related mechanotransduction. METHODS: By ligating the left coronary artery of rats to establish an in vivo model of chronic myocardial infarction (MI), lentivirus-mediated thoracic dorsal root ganglion (TDRG)-specific Piezo1 knockdown rats and adeno-associated virus-PHP.S-mediated TDRG neuron-specific Piezo1 knockout mice were used to investigate whether Piezo1 in the TDRG plays a functional role during ventricular remodeling. Subsequently, neutralizing antibody-mediated TDRG IL-6 (interleukin-6) inhibition rats and adeno-associated virus-PHP.S-mediated TDRG neuron-specific IL-6 knockdown mice were used to determine the mechanism underlying neurogenic inflammation. Primary TDRG neurons were used to evaluate Piezo1 function in vitro. RESULTS: Expression of Piezo1 and IL-6 was increased, and these factors were functionally activated in TDRG neurons at 4 weeks after MI. Both knockdown of TDRG-specific Piezo1 and deletion of TDRG neuron-specific Piezo1 lessened the severity of ventricular remodeling at 4 weeks after MI and decreased the level of IL-6 in the TDRG or heart. Furthermore, inhibition of TDRG IL-6 or knockdown of TDRG neuron-specific IL-6 also ameliorated ventricular remodeling and suppressed the IL-6 cascade in the heart, whereas the Piezo1 level in the TDRG was not affected. In addition, enhanced Piezo1 function, as reflected by abundant calcium influx induced by Yoda1 (a selective agonist of Piezo1), led to increased release of IL-6 from TDRG neurons in mice 4 weeks after MI. CONCLUSIONS: Our findings point to a critical role for Piezo1 in ventricular remodeling at 4 weeks after MI and reveal a neurogenic inflammatory cascade as a previously unknown facet of the neuronal immune signaling axis underlying mechanotransduction.

Lysophosphatidic acid contributes to myocardial ischemia/reperfusion injury by activating TRPV1 in spinal cord.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that plays a crucial role in cardiovascular diseases. Here, we question whether LPA contributes to myocardial ischemia/reperfusion (I/R) injury by acting on transient receptor potential vanilloid 1 (TRPV1) in spinal cord. By ligating the left coronary artery to establish an in vivo I/R mouse model, we observed a 1.57-fold increase in LPA level in the cerebrospinal fluid (CSF). The I/R-elevated CSF LPA levels were reduced by HA130, an LPA synthesis inhibitor, compared to vehicle treatment (4.74 ± 0.34 vs. 6.46 ± 0.94 µg/mL, p = 0.0014). Myocardial infarct size was reduced by HA130 treatment compared to the vehicle group (26 ± 8% vs. 46 ± 8%, p = 0.0001). To block the interaction of LPA with TRPV1 at the K710 site, we generated a K710N knock-in mouse model. The TRPV1K710N mice were resistant to LPA-induced myocardial injury, showing a smaller infarct size relative to TRPV1WT mice (28 ± 4% vs. 60 ± 7%, p < 0.0001). Additionally, a sequence-specific TRPV1 peptide targeting the K710 region produced similar protective effects against LPA-induced myocardial injury. Blocking the K710 region through K710N mutation or TRPV1 peptide resulted in reduced neuropeptides release and decreased activity of cardiac sensory neurons, leading to a decrease in cardiac norepinephrine concentration and the restoration of intramyocardial pro-survival signaling, namely protein kinase B/extracellular regulated kinase/glycogen synthase kinase-3ß pathway. These findings suggest that the elevation of CSF LPA is strongly associated with myocardial I/R injury. Moreover, inhibiting the interaction of LPA with TRPV1 by blocking the K710 region uncovers a novel strategy for preventing myocardial ischemic injury.

Plasma exosomes generated by ischaemic preconditioning are cardioprotective in a rat heart failure model.

BACKGROUND: Exosomes released into the plasma after brief cardiac ischaemia mediate subsequent cardioprotection. Whether donor exosomes can provide cardioprotection to recipients with chronic heart failure, which confers the highest perioperative risk, is unknown. We examined whether ischaemic preconditioning (IPC)-induced plasma exosomes exerted cardioprotection after their transfer from normal donors to post-infarcted failing hearts. METHODS: Plasma exosomes were obtained from adult rats after IPC or sham. An exosome inhibitor GW4869 was administrated before IPC in an in vivo model of ischaemia/reperfusion (I/R) injury in normal rats. The IPC exosomes or control exosomes from normal donor rats were perfused to the normal or post-infarcted failing rat hearts before ischaemia in Langendorff perfusion experiments. Infarct size, cardiac enzymes, cardiac function, and pro-survival kinases were quantified. RESULTS: The IPC stimulus increased the release of exosomes, whereas GW4869 inhibited the rise of plasma exosomes. Pre-treatment with GW4869 reversed IPC-mediated cardioprotection against in vivo I/R injury. In the Langendorff perfusion experiments, IPC exosomes from normal donor rats reduced mean infarct size from 41.05 (1.87)% to 31.43 (1.81)% and decreased lactate dehydrogenase activity in the post-infarcted failing rat hearts. IPC exosomes but not control exosomes activated pro-survival kinases in the heart tissues. CONCLUSIONS: Ischaemic preconditioning-induced exosomes from normal rats can restore cardioprotection in heart failure after myocardial infarction, which is associated with activation of pro-survival protein kinases. These results suggest a potential perioperative therapeutic role for ischaemic preconditioning-induced exosomes.

Spinal cord astrocytes regulate myocardial ischemia-reperfusion injury.

Astrocytes play a key role in the response to injury and noxious stimuli, but its role in myocardial ischemia-reperfusion (I/R) injury remains largely unknown. Here we determined whether manipulation of spinal astrocyte activity affected myocardial I/R injury and the underlying mechanisms. By ligating the left coronary artery to establish an in vivo I/R rat model, we observed a 1.7-fold rise in glial fibrillary acidic protein (GFAP) protein level in spinal cord following myocardial I/R injury. Inhibition of spinal astrocytes by intrathecal injection of fluoro-citrate, an astrocyte inhibitor, decreased GFAP immunostaining and reduced infarct size by 29% relative to the I/R group. Using a Designer Receptor Exclusively Activated by Designer Drugs (DREADD) chemogenetic approach, we bi-directionally manipulated astrocyte activity employing GFAP promoter-driven Gq- or Gi-coupled signaling. The Gq-DREADD-mediated activation of spinal astrocytes caused transient receptor potential vanilloid 1 (TRPV1) activation and neuropeptide release leading to a 1.3-fold increase in infarct size, 1.2-fold rise in serum norepinephrine level and higher arrhythmia score relative to I/R group. In contrast, Gi-DREADD-mediated inhibition of spinal astrocytes suppressed TRPV1-mediated nociceptive signaling, resulting in 35% reduction of infarct size and 51% reduction of arrhythmia score from I/R group, as well as lowering serum norepinephrine level from 3158 ± 108 to 2047 ± 95 pg/mL. Further, intrathecal administration of TRPV1 or neuropeptide antagonists reduced infarct size and serum norepinephrine level. These findings demonstrate a functional role of spinal astrocytes in myocardial I/R injury and provide a novel potential therapeutic approach targeting spinal cord astrocytes for the prevention of cardiac injury.

Interleukin-6 trans-signalling in hippocampal CA1 neurones mediates perioperative neurocognitive disorders in mice.

BACKGROUND: Interleukin-6 (IL-6), a pleiotropic cytokine with both degenerative and regenerative properties, is necessary and sufficient to provoke perioperative neurocognitive disorders after aseptic trauma in mice. IL-6 initiates its actions after binding to either membrane-bound IL-6 receptor α (mIL-6Rα) through classical signalling, or soluble IL-6 receptor (IL-6R) through trans-signalling; both signalling pathways require the transducer gp130. We investigated the site and type of IL-6 signalling that pertains in a tibial fracture aseptic trauma model of perioperative neurocognitive disorder. METHODS: Wild-type or genetically altered adult mice that lacked molecules unique to either classical or trans-IL-6 signalling underwent tibial fracture under isoflurane anaesthesia. In separate cohorts, we assessed postoperative memory using a trace fear conditioning paradigm (72 h postoperatively), and post-receptor IL-6 signalling (24 h postoperatively) using phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) in CA1 hippocampal neurones. Fracture healing was assessed at postoperative day 15 after inhibiting either both forms of IL-6 signalling with BE0047 or only trans-signalling with sgp130Fc. RESULTS: The surgical phenotype of memory decline (decrease in freezing in trace fear conditioning) and upregulated IL-6 signalling (pSTAT3) did not occur after pretreatment before surgery with either BE0047 or sgp130Fc, or after depleting gp130 from CA1 neurones. The surgical phenotype still occurred when IL-6Rα was depleted in either CA1 hippocampal neurones (freezing time, 38.9% [11.5%] vs 58.4% [12.3%]; pSTAT+ CA1 neurones, 31.7 [4.9] vs 7.0 [3.1]) or microglia (freezing time, 40.1% [13.9%] vs 65.2% [12.6%]; pSTAT+ CA1 neurones, 30.1 [5.5] vs 7.9 [3.2]). In global IL-6Rα-/- mice, hyper-IL-6, the trans-signalling agonist, produced the surgical phenotype when administered i.c.v. (freezing time, 42.4% [8.8%] vs 59.7% [10.4%]; pSTAT+ cells, 29.3 [4.3] vs 10.0 [4.4]). Bone-fracture healing (% of fracture callus comprised of new collagen) was significantly greater with sgp130Fc than with BE0047 (52.2% [8.3%] vs 39.7% [7.9%]). CONCLUSIONS: After orthopaedic trauma, IL-6 produces perioperative neurocognitive disorders through IL-6 trans-signalling in mouse CA1 neurones. Druggable targets of the trans-signalling pathway should be sought to reduce perioperative neurocognitive disorders while allowing the healing properties of classical IL-6 signalling.

V1-Cal hydrogelation enhances its effects on ventricular remodeling reduction and cardiac function improvement post myocardial infarction.

Myocardial infarction (MI) is a major cause of disability and mortality worldwide. A cell permeable peptide V1-Cal has shown remarkable therapeutic effects on ML However, using V1-Cal to improve long-term cardiac function after MI is presently limited by its short half-life. Herein, we co-assembled V1-Cal with a well-known hydrogelator Nap-Phe-Phe-Tyr (NapFFY) to obtain a new supramolecular hydrogel V1-Cal/NapFFY. We found that the hydrogel could significantly enhance the therapeutic effects of V1-Cal on ventricular remodeling reduction and cardiac function improvement in a myocardial infarction rat model. In vitro experiments indicated that co-assembly of V1-Cal with NapFFY significantly increased mechanic strength of the hydrogel, enabling a sustained release of V1-Cal for more than two weeks. In vivo experiments supported that sustained release of V1-Cal from V1-Cal/NapFFY hydrogel could effectively decrease the expression and activation of TRPV1, reduce apoptosis and the release of inflammatory factors in a MI rat model. In particular, V1-Cal/NapFFY hydrogel significantly decreased infarct size and fibrosis, while improved cardiac function 28 days post MI. We anticipate that V1-Cal/NapFFY hydrogel could be used clinically to treat MI in the near future.

Two insulin receptors determine alternative wing morphs in planthoppers.

Wing polyphenism is an evolutionarily successful feature found in a wide range of insects. Long-winged morphs can fly, which allows them to escape adverse habitats and track changing resources, whereas short-winged morphs are flightless, but usually possess higher fecundity than the winged morphs. Studies on aphids, crickets and planthoppers have revealed that alternative wing morphs develop in response to various environmental cues, and that the response to these cues may be mediated by developmental hormones, although research in this area has yielded equivocal and conflicting results about exactly which hormones are involved. As it stands, the molecular mechanism underlying wing morph determination in insects has remained elusive. Here we show that two insulin receptors in the migratory brown planthopper Nilaparvata lugens, InR1 and InR2, have opposing roles in controlling long wing versus short wing development by regulating the activity of the forkhead transcription factor Foxo. InR1, acting via the phosphatidylinositol-3-OH kinase (PI(3)K)-protein kinase B (Akt) signalling cascade, leads to the long-winged morph if active and the short-winged morph if inactive. InR2, by contrast, functions as a negative regulator of the InR1-PI(3)K-Akt pathway: suppression of InR2 results in development of the long-winged morph. The brain-secreted ligand Ilp3 triggers development of long-winged morphs. Our findings provide the first evidence of a molecular basis for the regulation of wing polyphenism in insects, and they are also the first demonstration--to our knowledge--of binary control over alternative developmental outcomes, and thus deepen our understanding of the development and evolution of phenotypic plasticity.

Approximation of a melting plateau of large area HTFP cells used for spectral irradiance realization.

This paper adopted an approximation of a melting plateau to solve the problem that temperature data cannot be monitored continuously when measuring the spectral irradiance of a large area tungsten carbide-carbon high-temperature fixed-point blackbody at each measured wavelength. Tests with fully measured curves showed that the method has a rather small deviation from the measured data of 0.017 K maximum, which corresponds to the spectral irradiance deviation of 0.005% at 500 nm. The maximum relative deviation between the Akima fitting method and the measured temperature in terms of spectral irradiance was 0.002%, which was better than -0.067% of a single temperature of 3020.11 K method and 0.026% of a linear interpolation method.

Inhibition of DRG-TRPV1 upregulation in myocardial ischemia contributes to exogenous cardioprotection.

Myocardium ischemia-reperfusion injury (IRI) is the major cause of postoperative cardiac dysfunction. While intrathecal morphine preconditioning (ITMP) can reduce IRI in animals, the molecular processes underlying IRI and ITMP remain elusive. Transient receptor potential vanilloid type 1 (TRPV1) is highly expressed in cardiac sensory neurons and has a crucial role in detecting myocardial ischemia. This study aimed to determine the role of up-regulated dorsal root ganglion (DRG)-TRPV1 in IRI and whether its inhibition contributes to ITMP-induced cardioprotection. Animal model of IRI was established by left coronary artery occlusion (30 min) and reperfusion (2 h) in rats. Intrathecal intubation was prepared for morphine preconditioning, TRPV1-shRNA or selective TRPV1 antagonist administration. After IRI, both protein and phosphorylation levels of TRPV1 were significantly increased, and the immunofluorescence intensity of TRPV1 was increased and colocalized with µ-opioid receptors in DRG. Intrathecal pre-administration of either TRPV1-shRNA or TRPV1 antagonist significantly reduced myocardial injury and the upregulation of TRPV1 in DRG induced by IRI. Simultaneously, ITMP significantly suppressed TRPV1 protein expression and phosphorylation in DRG, as well as the heart infarct size and arrhythmia score caused by IRI. The suppression of TRPV1 elevation and activation by ITMP were reversed by intrathecal injection of the selective µ receptor antagonist. Furthermore, IRI elevated DRG cAMP, while intrathecal administration of the selective cAMP-PKA inhibitor reduced myocardial injury. Finally, we showed that activation of opioid receptor by morphine inhibited PKA activator-induced TRPV1 channel activity at the cellular level. These findings suggest that the elevation and activation of TRPV1 in DRG during myocardial ischemia-reperfusion might be responsible for cardiac injury. ITMP exerts cardioprotection by inhibiting DRG-TRPV1 activity via modulation cAMP. Therefore, inhibition of TRPV1 upregulation in DRG might be used as a novel therapeutic mechanism for myocardium ischemia-reperfusion injury.

Role of vergence eye movements in the visual recognition of long time duration.

When viewing dichoptic stimuli in long time duration, visual percepts are always the alternation between the left and right eye inputs, while not the combination. This is known as binocular rivalry. An efficient coding theory reported that binocular visual inputs can be combined into binocular summation (S+) and difference (S-) channels in V1 brain area. In this study, we used specially designed stimuli as the previous study, in which monocular inputs caused ambiguous percepts, but S+ and S- channels had unambiguous percepts. We aim to investigate whether the visual percepts alter between S+ and S- channels in long time duration and whether vergence eye movements are involved in the process. To do so, the stimuli were presented in 300-s time duration in a trial, and a binocular eye tracker was used to record eye information. Participants' real-time behavioral responses about the visual percepts and binocular information were recorded simultaneously. The results show there are perceptual flips between S+ and S- channels in both central and long time viewing conditions. More importantly, in central vision there are vergence eye movements before perceptual flips, suggesting the involvement of high level visual attention; the time of a perceptual flip from S+ is shorter than that of a flip from S-, which might be due to different involvements of visual attention, indicating a bias of feedback connection from higher brain areas for visual attention to S+ channel. Since S+ and S- dominated signals can be carried by different types of binocular neurons, our results provide new insights into high level visual attention and binocular neurons in V1 brain area by using specially designed dichoptic stimuli and eye vergence as measuring tools.

A method for spectral irradiance measurement based on a large area WC-C fixed point blackbody.

We have proposed a novel method for the spectral irradiance measurement of the standard lamp. The measurement has been realized by using national primary scale based on a large area WC-C fixed point blackbody for the first time. The wavelength range is from 450 nm to 1000 nm. The spectral irradiance of the standard lamp has been measured based on the traditional variable temperature blackbody and large area WC-C fixed point blackbody. The results of the two methods agree within the uncertainties. Compared with the traditional measurement method, the fixed point method can reduce the major component of the spectral irradiance measurement uncertainty related to the temperature measurement.

A method for optimizing the reference temperature in the effective emissivity calculation of nonisothermal blackbody cavities.

For a nonisothermal blackbody cavity, different reference temperatures have influence on the calculation of effective emissivity. Previous studies proposed a weighted average method which can be indicated by a priori to calculate the reference temperature. However, these studies did not mention how to define the weight function but used some arbitrary temperature or the temperature of a fixed position like the central bottom of the cavity as the reference temperature. In this study, a quantitative analysis and calculation method, which is implemented in the Monte Carlo method based optical simulation software Tracepro, is proposed to define the weight coefficients and optimize the reference temperature. To do so, in the Tracepro software, a surface source is placed in front of the cavity opening and emits radiation to the blackbody cavity. The radiation from this surface source can be absorbed or reflected many times in the cavity, and finally the incident radiation distribution in the cavity can be obtained. According to the principle of light path reversibility, the normalized incident radiation can be considered as the contribution of its position to the effective emissivity. In the experiment, the actual temperatures of two different-shaped blackbody cavities are measured with the non-contact method in 873 K temperature. By dividing the inner surface of each blackbody cavity into several regions based on the positions of the actually measured temperature points, the incident radiation from the surface source to each segmented region is calculated and normalized to the total incident radiation across all regions as its weight coefficient; the reference temperature is the sum of the weighted temperature (by multiplying each weight coefficient with its measured temperature) in each region. Different from previous studies, this study optimizes the reference temperature by considering the contribution of the whole cavity to the effective emissivity, which should be more consistent with the actual situation. Moreover, the influences of different shapes of the blackbody cavities, different radiation characteristics of the inner surface materials and different viewing conditions of the effective emissivity on the reference temperature are discussed and compared. The results suggest that the optimization of reference temperature has close link with above factors and thus should be calculated individually.

Author Correction: Delivery of acetylthevetin B, an antitumor cardiac glycoside, using polymeric micelles for enhanced therapeutic efficacy against lung cancer cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Spectral irradiance primary scale realization and characterization of deuterium lamps from 200 to 400 nm.

To meet the increasing metrology demand of spectral irradiance in the short UV spectral range, a new spectral irradiance scale from 200 to 400 nm was realized at National Institute of Metrology (NIM) based on a high-temperature blackbody BB3500M, and a group of stable deuterium lamps are used as the transfer standards. Accurate real-time temperature of a blackbody is derived to reduce the temperature drift during the measurement period. A combination of an absolute and relative measurement system is designed to reduce repeatability uncertainty, and a selective optical filter method is used to remove fluorescence with a peak at 330 nm. A seven-point bandwidth novel correction method based on differential quadrature formula is put forward to correct the bandwidth error of the monochromator. The expanded uncertainties of the new spectral irradiance scale are 5.3% at 200 nm, 1.8% at 250 nm, 1.9% at 330 nm, and 3.6% at 400 nm, respectively. In the overlap wavelength from 250 to 400 nm, the average deviation between two types transfer standards, deuterium lamps and tungsten halogen lamps, is verified to be 0.39%, which are consistent with the associated measurement uncertainties.

Analysis and improvements of effective emissivities of nonisothermal blackbody cavities.

The emissivity of the blackbody is a very important parameter in spectral radiance measurement systems. In the conventional method, the emissivity is calculated based on the isothermal model. However, the actual temperature distribution in the blackbody cavity is always nonisothermal; the emissivity calculated based on the isothermal model may not accurately present the radiation characteristic of the blackbody. In this study, the actual temperature distributions of two blackbodies (one has an extended cone shape, and the other a 65-mm diameter cylindrical shape) are measured, and the emissivities are calculated accordingly based on the nonisothermal model at a certain temperature (873 K). The results show there are different tendencies of temperature distributions in the two blackbodies. When compared with the isothermal model, the emissivities in the 873 K temperature and 2.0-20.0 µm wavelength condition are about 1.75% and 0.18% lower at the nonisothermal model for the extended cone shape and cylindrical blackbodies, respectively. To improve the emissivity, different types of apertures are customized for the two blackbodies. For the extended cone-shaped blackbody, the emissivity in the 873 K temperature and 2.0-20.0 µm wavelength condition increases by 1.12% when using a ring-shaped graphite aperture in the cavity, whereas for the cylindrical-shaped blackbody, the emissivity in the same condition increases by 0.09% when using a high-reflective aperture in front of the cavity opening. Different from previous studies, this study provides new insight in calculating and improving the effective emissivity of blackbodies by using the measured temperature in the cavity based on the nonisothermal model.

Invalid-Resource-Aware Spectrum Assignment for Advanced-Reservation Traffic in Elastic Optical Network.

Elastic optical networks (EONs) can make service accommodation more flexible and precise by employing efficient routing and spectrum allocation (RSA) algorithms. In order to improve the efficiency of RSA algorithms, the advanced-reservation technique was introduced into designing RSA algorithms. However, few of these advanced-reservation-based RSA algorithms were focused on the unavailable spectrum resources in EONs. In this paper, we propose an Advanced-Reservation-based Invalid-Spectrum-Aware (AR-ISA) resource allocation algorithm to improve the networking performance and the resource alignment of EONs. By employing a new index, Invalid Spectrum Rate (ISR), to record the proportion of unavailable spectrum resources in EONs, the proposed AR-ISA algorithm set a network load threshold to trigger the postponement of an arriving service. Compared with the traditional slack-based AR mechanism, the proposed algorithm has more concerns about the current spectrum usage of the path designated by the service than the conflicts between AR services and other existing services. To further increase the networking performance, the proposed algorithm adopts defragmentation to increase the number of available spectrum resources when postponing a service. Theoretical analysis and simulation results show that the proposed AR-ISA algorithm has obvious effectiveness in reducing the service blocking rate and increasing the spectrum alignment rate.

Intrathecal lentivirus-mediated RNA interference targeting nerve growth factor attenuates myocardial ischaemia-reperfusion injury in rat.

BACKGROUND: Nerve growth factor (NGF) has been implicated in hyperalgesia by sensitising nociceptors. A role for NGF in modulating myocardial injury through ischaemic nociceptive signalling is plausible. We examined whether inhibition of spinal NGF attenuates myocardial ischaemia-reperfusion injury and explored the underlying mechanisms. METHODS: In adult rats, lentivirus-mediated short-hairpin RNA targeted at reducing NGF gene expression (NGF-shRNA) or a transient receptor potential vanilloid 1 (TRPV1) antagonist (capsazepine) was injected intrathecally before myocardial ischaemia-reperfusion. Infarct size (expressed as the ratio of area at risk) and risk of arrhythmias were quantified. Whole-cell clamp patch electrophysiology was used to record capsaicin currents in primary dorsal root ganglion neurones. The co-expression of substance P (SP) and calcitonin gene-related peptide (CGRP), plus activation of TRPV1, protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) were also quantified. RESULTS: NGF levels increased by 2.95 (0.34)-fold in dorsal root ganglion and 2.12 (0.27)-fold in spinal cord after myocardial ischaemia-reperfusion injury. Intrathecal injection of NGF-shRNA reduced infarct area at risk from 0.58 (0.02) to 0.37 (0.02) (P<0.01) and reduced arrhythmia score from 3.67 (0.33) to 1.67 (0.33) (P<0.01). Intrathecal capsazepine was similarly cardioprotective. NGF-shRNA suppressed expression of SP/CGRP and activation of Akt/ERK and TRPV1 in spinal cord. NGF increased capsaicin current amplitude from 144 (42) to 840 (132) pA (P<0.05), which was blocked by the TRPV1 antagonist 5'-iodoresiniferatoxin. Exogenous NGF enhanced capsaicin-induced Akt/ERK and TRPV1 activation in PC12 neuroendocrine tumour cells in culture. CONCLUSIONS: Spinal NGF contributes to myocardial ischaemia-reperfusion injury by mediating nociceptive signal transmission.

Lipid-Based Liquid Crystalline Nanoparticles Facilitate Cytosolic Delivery of siRNA via Structural Transformation.

RNA interference (RNAi) technology has shown great promise for the treatment of cancer and other genetic disorders. Despite the efforts to increase the target tissue distribution, the safe and effective delivery of siRNA to the diseased cells with sufficient cytosolic transport is another critical factor for successful RNAi clinical application. Here, the constructed lipid-based liquid crystalline nanoparticles, called nano-Transformers, can transform thestructure in the intracellular acidic environment and perform high-efficient siRNA delivery for cancer treatment. The developed nano-Transformers have satisfactory siRNA loading efficiency and low cytotoxicity. Different from the traditional cationic nanocarriers, the endosomal membrane fusion induced by the conformational transition of lipids contributes to the easy dissociation of siRNA from nanocarriers and direct release of free siRNA into cytoplasm. We show that transfection with cyclin-dependent kinase 1 (CDK1)-siRNA-loaded nano-Transformers causes up to 95% reduction of relevant mRNA in vitro and greatly inhibits the tumor growth without causing any immunogenic response in vivo. This work highlights that the lipid-based nano-Transformers may become the next generation of siRNA delivery system with higher efficacy and improved safety profiles.

Large-aperture UV (250~400 nm) imaging spectrometer based on a solid Sagnac interferometer.

Developing an ultraviolet (UV) imaging spectrometer is challenging due to a low level of incident power of photon flux, large chromatic aberration, and relatively low quantum efficiency of imaging sensor in UV waveband. In this paper, a large-aperture UV (250~400 nm) Fourier transform imaging spectrometer is presented for close-range hyperspectral sensing with high spatial resolution and decent spectral resolution. An advanced design based on a modified solid Sagnac interferometer working in UV waveband of 250~400 nm is introduced to improve the interferometric stability. A large-aperture and a reflective-transmissive filtering system are used to increase the spectral purity of the incident UV radiation, and air-spaced achromatic doublets are designed to address the chromatic aberration. The finished spectrometer has a spatial resolution of 23.44 µm on the target plane, a wavelengths resolution of 1.59 nm at 250 nm, and can provide approximately 59 wavelength samples over the waveband of 250~400 nm. The proposed imaging spectrometer acquires a hyperspectral data cube through push-broom scanning in a few minutes. Examples of UV hyperspectral imaging are demonstrated with a sample of resolution test chart, and a cotton sample with vitamin C (VC) and vitamin B6 (VB6) traces. Based on the analysis of spectra, monochromatic images, and k-Means clustering results, it can be concluded that the spectrometer is capable of UV hyperspectral imaging with excellent spectral accuracy, spatial performance, compactness, and robustness. The potential applications of the proposed instrument include materials analysis and traces detection with UV spectral characteristics.

Delivery of acetylthevetin B, an antitumor cardiac glycoside, using polymeric micelles for enhanced therapeutic efficacy against lung cancer cells.

Acetylthevetin B (ATB), a cardiac glycoside from the seed of Thevetia peruviana (Pers) K Schum (yellow oleander), exhibits not only antitumor activity but also potential cardiac toxicity. In the present study, we attempted to enhance its antitumor action and decrease its adverse effects via chitosan-Pluronic P123 (CP) micelle encapsulation. Two ATB-loaded CP micelles (ATB-CP1, ATB-CP2) were prepared using an emulsion/solvent evaporation technique. They were spherical in shape with a particle size of 40-50 nm, showed a neutral zeta potential, and had acceptable encapsulation efficiency (>90%). Compared to the free ATB (IC50=2.94 µmol/L), ATB-loaded CP micelles exerted much stronger cytotoxicity against human lung cancer A549 cells with lower IC50 values (0.76 and 1.44 µmol/L for ATB-CP1 and ATB-CP2, respectively). After administration of a single dose in mice, the accumulation of ATB-loaded CP1 micelles in the tumor and lungs, respectively, was 15.31-fold and 9.49-fold as high as that of free ATB. A549 xenograft tumor mice treated with ATB-loaded CP1 micelles for 21 d showed the smallest tumor volume (one-fourth of that in the control group) and the highest inhibition rate (85.6%) among all the treatment groups. After 21-d treatment, no significant pathological changes were observed in hearts and other main tissues. In summary, ATB may serve as a promising antitumor chemotherapeutic agent for lung cancer, and its antitumor efficacy was significantly improved by CP micelles, with lower adverse effects.