Population pharmacokinetics of daptomycin in critically ill patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations. METHODS: A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations. RESULTS: Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are  ≥1 mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCR > 30 mL/min. Our simulations suggest 10 mg/kg for patients with CLCR between 30 and 90 mL/min, and 12 mg/kg for patients with CLCR higher than 90 mL/min. CONCLUSIONS: This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.

Generating complex vectorial optical fields via surface lattice resonances.

Vectorial optical fields (VOFs) with extra degrees of freedom hold promise for many photonic applications. However, current methods to generate VOFs are either bulky in size or exhibit limited functionalities. Here, we demonstrate a tunable VOF generator by exciting plasmonic surface lattice resonances (SLRs) with axial symmetry. By meticulously arranging bilayer circular arrays with opposite handedness, we achieve a high Q-factor of 103 via just a few particles despite the general belief that too small array size suppresses the SLRs. This work presents tunable complex VOFs with distinct inhomogeneous spatial polarization distributions, which may enable various applications in integrated and polarization optics.

Glia-derived adenosine in the ventral hippocampus drives pain-related anxiodepression in a mouse model resembling trigeminal neuralgia.

Glial activation and dysregulation of adenosine triphosphate (ATP)/adenosine are involved in the neuropathology of several neuropsychiatric illnesses. The ventral hippocampus (vHPC) has attracted considerable attention in relation to its role in emotional regulation. However, it is not yet clear how vHPC glia and their derived adenosine regulate the anxiodepressive-like consequences of chronic pain. Here, we report that chronic cheek pain elevates vHPC extracellular ATP/adenosine in a mouse model resembling trigeminal neuralgia (rTN), which mediates pain-related anxiodepression, through a mechanism that involves synergistic effects of astrocytes and microglia. We found that rTN resulted in robust activation of astrocytes and microglia in the CA1 area of the vHPC (vCA1). Genetic or pharmacological inhibition of astrocytes and connexin 43, a hemichannel mainly distributed in astrocytes, completely attenuated rTN-induced extracellular ATP/adenosine elevation and anxiodepressive-like behaviors. Moreover, inhibiting microglia and CD39, an enzyme primarily expressed in microglia that degrades ATP into adenosine, significantly suppressed the increase in extracellular adenosine and anxiodepressive-like behaviors. Blockade of the adenosine A2A receptor (A2AR) alleviated rTN-induced anxiodepressive-like behaviors. Furthermore, interleukin (IL)-17A, a pro-inflammatory cytokine probably released by activated microglia, markedly increased intracellular calcium in vCA1 astrocytes and triggered ATP/adenosine release. The astrocytic metabolic inhibitor fluorocitrate and the CD39 inhibitor ARL 67156, attenuated IL-17A-induced increases in extracellular ATP and adenosine, respectively. In addition, astrocytes, microglia, CD39, and A2AR inhibitors all reversed rTN-induced hyperexcitability of pyramidal neurons in the vCA1. Taken together, these findings suggest that activation of astrocytes and microglia in the vCA1 increases extracellular adenosine, which leads to pain-related anxiodepression via A2AR activation. Approaches targeting astrocytes, microglia, and adenosine signaling may serve as novel therapies for pain-related anxiety and depression.

Development and implementation of a novel mechanized planting method for ecological restoration of aquatic environments using degradable nutrition pots.

Submerged plants play a significant role in the remediation and purification of polluted water bodies. Reconstruction of submerged plants has been considered as an important ecological method to restore aquatic ecosystems. However, large-scale and efficient plantation of submerged plants in water restoration is a huge challenge. This paper proposes a novel mechanized planting method for submerged plants utilizing nutrition pots as planting units. Firstly, the details of the mechanized planting method were introduced. The mechanized planting method involves pre-planting the reproductive bodies of submerged plants in degradable nutrition pots, and then implanting them into the underwater soil through a planting device. Secondly, the interaction force between the nutrition pot and the soil was measured. It was found that the implantation force of nutrition pots increases with planting velocity. The planting force shows a significant increase trend when the water content in the soil decreases. Thirdly, the deformation of the nutrition pot was studied through simulations. It was discovered that the deformation of the nutrition pot mainly occurs at the bottom and the side walls near the bottom, and the limited deformation ensures the integrity of the nutrition pot. Finally, a planting device with a linear motion mechanism was designed, and a typical submerged plant, Vallisneria natans was tested, using agricultural paper seedling containers as the nutrition pots. It was demonstrated that the mechanized device successfully planted submerged plant nutrition pots into the soil, and the submerged plants survived and showed a clear growth trend. The mechanized planting method of submerged plants proposed in this article is expected to provide a new and friendly technology for ecological restoration of water source.

P2X7 receptor is required for the ototoxicity caused by aminoglycoside in developing cochlear hair cells.

Aminoglycoside antibiotics (AGAs) are widely used in life-threatening infections, but they accumulate in cochlear hair cells (HCs) and result in hearing loss. Increases in adenosine triphosphate (ATP) concentrations and P2X7 receptor expression were observed after neomycin treatment. Here, we demonstrated that P2X7 receptor, which is a non-selective cation channel that is activated by high ATP concentrations, may participate in the process through which AGAs enter hair cells. Using transgenic knockout mice, we found that P2X7 receptor deficiency protects HCs against neomycin-induced injury in vitro and in vivo. Subsequently, we used fluorescent gentamicin-Fluor 594 to study the uptake of AGAs and found fluorescence labeling in wild-type mice but not in P2rx7-/- mice in vitro. In addition, knocking-out P2rx7 did not significantly alter the HC count and auditory signal transduction, but it did inhibit mitochondria-dependent oxidative stress and apoptosis in the cochlea after neomycin exposure. We thus conclude that the P2X7 receptor may be linked to the entry of AGAs into HCs and is likely to be a therapeutic target for auditory HC protection.

Toward Antifragility: Social Defeat Stress Enhances Learning and Memory in Young Mice Via Hippocampal Synaptosome Associated Protein 25.

Social adversity not only causes severe psychological diseases but also may improve people's ability to learn and grow. However, the beneficial effects of social adversity are often ignored. In this study, we investigated whether and how social adversity affects learning and memory in a mouse social defeat stress (SDS) model. A total of 652 mice were placed in experimental groups of six to 23 mice each. SDS enhanced spatial, novelty, and fear memory with increased synaptosome associated protein 25 (SNAP-25) level and dendritic spine density in hippocampal neurons among young but not middle-aged mice. Chemogenetic inhibition of hippocampal CaMK2A+ neurons blocked SDS-induced enhancement of learning or memory. Knockdown of SNAP-25 or blockade of N-methyl-D-aspartate (NMDA) receptor subunit GluN2B in the hippocampus prevented SDS-induced learning memory enhancement in an emotion-independent manner. These findings suggest that social adversity promotes learning and memory ability in youths and provide a neurobiological foundation for biopsychological antifragility.

The Role of Glia Underlying Acupuncture Analgesia in Animal Pain Models: A Systematic Review and Meta-Analysis.

BACKGROUND: As a traditional Chinese therapy, acupuncture is proposed worldwide as a treatment for pain and other health problems, but findings on acupuncture analgesia have been inconsistent because of its variable modalities of therapeutic intervention. OBJECTIVE: This study aimed to evaluate the existing animal studies for evidence on acupuncture and its effect on glia in association with a reduction in pain conditions. METHODS: Literature searches were performed in four English- and Chinese-language databases (Web of Science, PubMed, EMBASE, and CNKI) on October 8, 2021. Included studies reported the pain outcome (e.g., paw withdrawal latency, paw withdrawal threshold) and glia outcome (e.g., glial marker GFPA, Iba1, and OX42) in pain-induced animals during acupuncture treatment. RESULTS: Fifty-two preclinical studies were included in the meta-analysis. A single acupuncture treatment in rodents had an analgesic effect, which was more effective in inflammatory pain than in neuropathic pain in the early phase of treatment. The analgesic efficacy became more curative after repeated acupuncture. Furthermore, acupuncture treatment could effectively inhibit the activity of astrocytes and microglia in both inflammatory pain and neuropathic pain in a time-course pattern. CONCLUSIONS: Acupuncture treatment improves analgesic effect in rodent pain conditions under the possible mechanism of glial inhibition. Therefore, these results provide an opportunity to evaluate the effectiveness of acupuncture analgesia and neuroinflammation in animal models to research further neurobiological mechanisms and to inform the design of future clinical trials. STUDY REGISTRATION: PROSPERO (ID: CRD42020196011).

The neuroprotective effects of GPR55 against hippocampal neuroinflammation and impaired adult neurogenesis in CSDS mice.

Depression is one of the most prevalent mental illnesses in the world today, and the onset of depression is usually accompanied by neuroinflammation and impaired adult neurogenesis. As a new potential member of the endocannabinoid (eCB) system, G protein coupled receptor 55 (GPR55) has been associated with mood regulation. However, the role of GPR55 in the pathophysiology of depression remains poorly understood. Thus, a 10-day chronic social defeat stress (CSDS) paradigm was utilized as an animal model of depression to explore the potential role of GPR55 in depression. After CSDS, the protein level of GPR55 decreased significantly, but the mRNA expression did not change significantly, highlighting that although the GPR55 protein was involved in the progression of the depression- and anxiety-like phenotypes, its mRNA was not. Additionally, depression- and anxiety-like behaviors were also accompanied by neuroinflammation and impaired adult neurogenesis in the hippocampus. Interestingly, O-1602, a GPR55 agonist, remarkably prevented the development of depression- and anxiety-like behaviors as well as hippocampal neuroinflammation and neurogenesis deficits induced by CSDS. However, after electroacupuncture (EA) alleviated depression- and anxiety-like behaviors induced by CSDS, treatment with a GPR55 antagonist (CID16020046) reversed this effect. Our research demonstrated that downregulation of GPR55 expression in the hippocampus might mediate CSDS-induced depression- and anxiety-like phenotypes, and activation and upregulation of GPR55, which might be correlated with its anti-inflammatory and subsequent neuroprotective effects, could be a potential treatment for depression.

Tight focusing properties and focal field tailoring of cylindrical vector beams generated from a linearly polarized coherent beam array.

We investigate the focusing properties of cylindrical vector beams (CVBs) generated from the combination of an array of beams, each with sub-apertures and controllable polarization. The analytical expression of the tight focusing field of the combined CVBs has been derived based on the Richard-Wolf vector diffraction integral. To obtain a desired focal spot size which includes efficient sidelobe suppression, the required parameters, such as the exit sub-aperture, numerical aperture and truncation parameter, have been studied in detail. The result shows that the combined CVB distribution has a good match with the theoretical ideal CVB distribution. However, compared with the ideal CVBs, the focal spot width produced by the combined radially polarized beams is smaller. With the increase of initial polarization rotation of sub-aperture, the focal spot width increases, and the focal shape shifts from Gaussian-like to a flat-topped distribution and then to an annular distribution. Furthermore, flexible focal field tailoring can also be realized by adjusting the initial polarization rotation of each sub-aperture. These results might provide a valuable reference for material processing, microlithography and multi-particle manipulation.

Protein Kinase C Lambda Mediates Acid-Sensing Ion Channel 1a-Dependent Cortical Synaptic Plasticity and Pain Hypersensitivity.

Chronic pain is a serious debilitating disease for which effective treatment is still lacking. Acid-sensing ion channel 1a (ASIC1a) has been implicated in nociceptive processing at both peripheral and spinal neurons. However, whether ASIC1a also contributes to pain perception at the supraspinal level remains elusive. Here, we report that ASIC1a in ACC is required for thermal and mechanical hypersensitivity associated with chronic pain. ACC-specific genetic deletion or pharmacological blockade of ASIC1a reduced the probability of cortical LTP induction and attenuated inflammatory thermal hyperalgesia and mechanical allodynia in male mice. Using cell type-specific manipulations, we demonstrate that ASIC1a in excitatory neurons of ACC is a major player in cortical LTP and pain behavior. Mechanistically, we show that ASIC1a tuned pain-related cortical plasticity through protein kinase C λ-mediated increase of membrane trafficking of AMPAR subunit GluA1 in ACC. Importantly, postapplication of ASIC1a inhibitors in ACC reversed previously established nociceptive hypersensitivity in both chronic inflammatory pain and neuropathic pain models. These results suggest that ASIC1a critically contributes to a higher level of pain processing through synaptic potentiation in ACC, which may serve as a promising analgesic target for treatment of chronic pain.SIGNIFICANCE STATEMENT Chronic pain is a debilitating disease that still lacks effective therapy. Ion channels are good candidates for developing new analgesics. Here, we provide several lines of evidence to support an important role of cortically located ASIC1a channel in pain hypersensitivity through promoting long-term synaptic potentiation in the ACC. Our results indicate a promising translational potential of targeting ASIC1a to treat chronic pain.

Distinct Function of Estrogen Receptors in the Rodent Anterior Cingulate Cortex in Pain-related Aversion.

BACKGROUND: Brain-derived estrogen is implicated in pain-related aversion; however, which estrogen receptors mediate this effect remains unclear. This study hypothesized that the different estrogen receptors in the rostral anterior cingulate cortex play distinct roles in pain-related aversion. METHODS: Formalin-induced conditioned place avoidance and place escape/avoidance paradigms were used to evaluate pain-related aversion in rodents. Immunohistochemistry and Western blotting were used to detect estrogen receptor expression. Patch-clamp recordings were used to examine N-methyl-D-aspartate-mediated excitatory postsynaptic currents in rostral anterior cingulate cortex slices. RESULTS: The administration of the estrogen receptor-ß antagonist 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP) or the G protein-coupled estrogen receptor-1 antagonist (3aS*,4R*,9bR*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15) but not the estrogen receptor-α antagonist 1,3-bis (4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride (MPP) into the rostral anterior cingulate cortex blocked pain-related aversion in rats (avoidance score, mean ± SD: 1,3-bis [4-hydroxyphenyl]-4-methyl-5-(4-[2-piperidinylethoxy] phenol)-1H-pyrazole dihydrochloride (MPP): 47.0 ± 18.9%, 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP): -7.4 ± 20.6%, and [3aS*,4R*,9bR*]-4-[6-bromo-1,3-benzodioxol-5-yl]-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15): -4.6 ± 17.0% vs. vehicle: 46.5 ± 12.2%; n = 7 to 9; P < 0.0001). Consistently, estrogen receptor-ß knockdown but not estrogen receptor-α knockdown by short-hairpin RNA also inhibited pain-related aversion in mice (avoidance score, mean ± SD: estrogen receptor-α-short-hairpin RNA: 26.0 ± 7.1% and estrogen receptor-ß-short-hairpin RNA: 6.3 ± 13.4% vs. control short-hairpin RNA: 29.1 ± 9.1%; n = 7 to 10; P < 0.0001). Furthermore, the direct administration of the estrogen receptor-ß agonist 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN) or the G protein-coupled estrogen receptor-1 agonist (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1) into the rostral anterior cingulate cortex resulted in conditioned place avoidance (avoidance score, mean ± SD: 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN): 35.3 ± 9.5% and (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1): 43.5 ± 22.8% vs. vehicle: 0.3 ± 14.9%; n = 8; P < 0.0001) but did not affect mechanical or thermal sensitivity. The activation of the estrogen receptor-ß/protein kinase A or G protein-coupled estrogen receptor-1/protein kinase B pathway elicited the long-term potentiation of N-methyl-D-aspartate-mediated excitatory postsynaptic currents. CONCLUSIONS: These findings indicate that estrogen receptor-ß and G protein-coupled estrogen receptor-1 but not estrogen receptor-α in the rostral anterior cingulate cortex contribute to pain-related aversion by modulating N-methyl-D-aspartate receptor-mediated excitatory synaptic transmission.

Consistency between optical coherence tomography and humphrey visual field for evaluating glaucomatous defects in high myopic eyes.

BACKGROUND: The study is to investigate the influence of high myopia on the consistency between optical coherence tomography (OCT) and visual field in primary open-angle glaucoma (POAG). METHODS: We enrolled 37 patients with POAG with high myopia (POAG-HM group), 27 patients with POAG without high myopia (POAG group), and 29 controls with high myopia (HM group). All subjects underwent Humphrey perimetry (30-2 and 10-2 algorithms). The peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thicknesses were measured using Cirrus HD-OCT. Spearman's rank correlation analysis was used to determine correlations between OCT and perimetric parameters. Agreement was analyzed by cross-classification and weighted κ statistics. RESULTS: In POAG group, the cross-classification analysis showed strong agreement between the inferior temporal GCIPL thickness and the mean sensitivity (MS) of 10-2 algorithms (κ = 0.5447, P = 0.0048), and good agreement between the superior and inferior RNFL thicknesses and 30-2 MS (κ = 0.4407 and 0.4815; P < 0.05). In the POAG-HM group, only the inferior temporal GCIPL thickness showed good agreement with 10-2 MS (κ = 0.3155, P = 0.0289) and none of the RNFL sectors were in good agreement with the corresponding MS. CONCLUSIONS: In POAG patients with high myopia, changes in macular measurements were in accordance with visual field defects, and RNFL thickness did not consistently decline with visual field defects due to the effects of high myopia. This study suggests that during diagnosis and follow-up of glaucoma with high myopia, more attention need to be focused on structure and functional defects in macular areas.

High-power vortex beam generation enabled by a phased beam array fed at the nonfocal-plane.

High-power vortex beams have extensive applications in optical communication, nonlinear frequency conversion, and laser processing. To overcome a single beam's power limitation, generating vortex beams, based on a phased beam array, is an intuitive idea that requires locking each beamlet's phase to a specific different value. Conventionally, the intensity profiles of the focal plane (far field) are used for extracting the cost functions in active phase control systems. However, as for generating vortex beams, the cost function extraction method at the focal plane suffers because the same intensity profile of the beam array could correspond to different phase distributions in near field. Thus, the accurate phase control signals are difficult to obtain. In this paper, a new concept of extracting cost functions at the non-focal-plane is firstly presented and analyzed in detail by numerical simulation. This cost function extraction method is an efficient way of generating vortex beams with different topological charges, including second-order Bessel-Gaussian beams. The new concept could provide a valuable reference and contribute to the practical implementation of generating vortex beams by coherent beam combining technology.

Self-focusing and group-velocity dispersion of pulsed laser beams in the inhomogeneous atmosphere.

We study self-focusing and group-velocity dispersion (GVD) effects in the inhomogeneous atmosphere on pulsed-laser space debris removal facilitated by a ground-based laser. It is found that changes of the pulse duration and the beam spot size with the propagation distance are noticeable due to the interplay of the GVD effect and the self-focusing effect, which is quite different from the behavior in the linear case. It is shown that the temporal pulse splitting may appear on the space debris, and the spatial side lobe usually appears together with the temporal pulse splitting. As compared with the linear case, the beam width and the pulse width on the debris target increase. On the other hand, crucial formulae of the modified focal length and the M2-factor for laser debris removal are also derived. It is found that the beam quality on the debris target becomes better if our modified focal length is adopted, and the beam quality on the debris target will be good if the value of M2-factor is less than 1.6.

Prefrontal AMPA receptors are involved in the effect of methylphenidate on response inhibition in rats.

Response inhibition is a critical executive control function in many species. Deficits in response inhibition have been observed in many disorders, eg, attention deficit/hyperactivity disorder (ADHD). The stop-signal task (SST) is a unique behavior task for evaluating response inhibition via measuring the covert latency of a stop process, and it is widely used in studies of humans, nonhuman primates and rodents. Methylphenidate (MPH; Ritalin®) is a psychostimulant that is widely used for the treatment of ADHD and that effectively improves response inhibition in individuals with ADHD and normal subjects. However, its mechanism of improving response inhibition remains unknown. In this study we adopted a rodent nose-poking version of the SST to examine response inhibition by estimating the stop signal reaction time (SSRT) in rats. Administration of MPH (1 mg/kg, sc) 25 min before the SST test exerted a baseline-dependent effect of MPH on response inhibition, ie, it shortened the SSRTs only in the rats with larger baseline SSRTs, thereby improving response inhibition in these rats. The effect of MPH on response inhibition remained 3 h after MPH administration. Co-administration of PP2 (1 mg/kg, sc), a Src-protein tyrosine kinase (Src-PTKs) inhibitor that inhibited the upregulation of glutamate receptor expression on the plasma membrane of the prefrontal cortex (PFC), abolished the MPH-caused improvement in response inhibition. Furthermore, intra-PFC infusion of a selective AMPAR antagonist.NASPM (0.3 mmol/L, per side) via stainless guide cannulas implanted earlier abolished the effect of MPH on SSRT. These results suggest that AMPA receptors in the PFC are involved in the effect of MPH on response inhibition in rats.

Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors.

BACKGROUND: In recent years, proinflammatory cytokine interleukin-1ß (IL-1ß) was considered to play a critical role in the pathogenesis of depression. In addition, P2X7 receptor (P2X7R), a member of the purinergic receptor family, which is predominantly present on microglia, as well as on astrocytes and neurons in lesser amounts in the central nervous system, was suggested to be involved in the processing and releasing of IL-1ß. Here, we investigated the role of P2X7R in the pathogenesis of depression. METHODS: Male Sprague-Dawley rats were subjected to chronic unpredictable stressors (CUS) for 3 weeks. At the end of week 1, 2, and 3, extracellular ATP, caspase 1, IL-1ß, and components and activation of NLRP3 inflammasome (nucleotide-binding, leucine-rich repeat, pyrin domain containing 3) were evaluated as biomarker of neuroinflammation. In separate experiments, the rats were microinjected with P2X7R agonists ATP, BzATP, and saline into the hippocampus, respectively, or exposed to CUS combined with hippocampal microinjection with P2X7R antagonist, BBG and A438079, and saline, respectively, for 3 weeks, followed by exposed to forced swimming test and open-field test. Moreover, we also evaluated the depressive and anxiety-like behavior of P2X7-null mice in forced swimming test, open-field test, and elevated plus maze. RESULTS: Along with stress accumulation, extracellular ATP, cleaved-caspase 1, IL-1ß, and ASC were significantly enhanced in the hippocampus, but P2X7R and NLRP3 were not. Immunoprecipitation assay indicated that along with the accumulation of stress, assembly of NLRP3 inflammasome and cleaved caspase 1 in NLRP3 inflammasome were significantly increased. Moreover, antagonists of P2X7R, either BBG or A438079, prevented the development of depressive-like behaviors induced by chronic unpredictable stress in rats. Meanwhile, we could not observe any depressive-like or anxiety-like behaviors of P2X7-null mice after they had been exposed to CUS. The results implied that P2X7 knockout could impede the development of depressive-like and anxiety-like behaviors induced by CUS. In contrast, chronic administration of agonists of P2X7R, either ATP or BzATP, could induce depressive-like behaviors. CONCLUSIONS: The activation of P2X7R and subsequent NLRP3 inflammasome in hippocampal microglial cells could mediate depressive-like behaviors, which suggests a new therapeutic target for the prevention and treatment of depression.

Self-focusing effect of annular beams propagating in the atmosphere.

The self-focusing effect of annular beams propagating in the atmosphere to assist delivering powerful laser beams from orbit to the ground is studied in detail. It is found the annular beam is compressed more strongly due to the self-focusing effect as the beam obscure ratio increases. On the other hand, the self-focusing effect between annular, flat-topped and Gaussian beams is compared. It is shown that the self-focusing effect on the annular beam is stronger than that on flat-topped and Gaussian beams. However, the threshold critical power values of annular, flat-topped and Gaussian beams should be in sequence from small to large. Furthermore, the expression of the B integral of annular beams propagating from orbit to the ground in the atmosphere is derived, and the fitting equation related to the B integral of annular beams for maximal compression without filamentation is presented.

Thermal blooming effect of laser beams propagating through seawater.

The thermal blooming effect of laser beams propagating through seawater is studied in detail by using the numerical simulation method. It is found that an increase of the salinity in the seawater causes the more severe thermal blooming. As compared with the wavelength, the absorption coefficient is the main factor that dominates the thermal blooming because the absorption coefficient is very high in the seawater. In the seawater the thermal blooming becomes more severe for the wavelength corresponding to the higher absorption coefficient. Furthermore, both the behavior of the thermal blooming effect and the main factor dominating the thermal blooming effect in the shallow sea region are different from those in the deep sea region. In the shallow sea region, the dependence of the thermal blooming on the depth is not monotonic as the time increases. However, in the deep sea region, the thermal blooming effect becomes more severe monotonously as the depth increases. The physical explanations for the main results obtained in this paper are presented.

[Molecular mechanisms of NMDA receptor-MAPK-CREB pathway underlying the involvement of the anterior cingulate cortex in pain-related aversion].

The pain experience includes a sensory-discriminative component and an emotional-affective component. The great progress in the genetic, molecular, cellular and systemic levels on the study of the sensory dimension of pain has been made. However, the study of the emotional components of pain is relatively backward. A line of clinic observations indicates that chronic pain and pain-related negative emotion affect the physical and mental health of patients. This review summarizes the main progress from our and other laboratories regarding the affective component of pain, elaborates the neuronal mechanisms of pain-related aversive emotion in the anterior cingulate cortex (ACC), especially the critical role of NMDA receptors and ERK-CREB pathway. A variety of regulatory molecules, such as synapse associated protein SIP30 and estrogen contribute to pain-related aversive emotion via facilitating presynaptic glutamate release and postsynaptic NMDA receptor-mediated synaptic transmission. The far-reaching effects of pain-related negative emotion on patients with chronic pain are emphasized.

Delayed activation of spinal microglia contributes to the maintenance of bone cancer pain in female Wistar rats via P2X7 receptor and IL-18.

Accumulating evidence suggests that activation of spinal microglia contributes to the development of inflammatory and neuropathic pain. However, the role of spinal microglia in the maintenance of chronic pain remains controversial. Bone cancer pain shares features of inflammatory and neuropathic pain, but the temporal activation of microglia and astrocytes in this model is not well defined. Here, we report an unconventional role of spinal microglia in the maintenance of advanced-phase bone cancer pain in a female rat model. Bone cancer elicited delayed and persistent microglial activation in the spinal dorsal horn on days 14 and 21, but not on day 7. In contrast, bone cancer induced rapid and persistent astrocytic activation on days 7-21. Spinal inhibition of microglia by minocycline at 14 d effectively reduced bone cancer-induced allodynia and hyperalgesia. However, pretreatment of minocycline in the first week did not affect the development of cancer pain. Bone cancer increased ATP levels in CSF, and upregulated P2X7 receptor, phosphorylated p38, and IL-18 in spinal microglia. Spinal inhibition of P2X7/p-38/IL-18 pathway reduced advanced-phase bone cancer pain and suppressed hyperactivity of spinal wide dynamic range (WDR) neurons. IL-18 induced allodynia and hyperalgesia after intrathecal injection, elicited mechanical hyperactivity of WDR neurons in vivo, and increased the frequency of mEPSCs in spinal lamina IIo nociceptive synapses in spinal cord slices. Together, our findings demonstrate a novel role of microglia in maintaining advanced phase cancer pain in females via producing the proinflammatory cytokine IL-18 to enhance synaptic transmission of spinal cord nociceptive neurons.