Electronic Metal-Support Interactions Boost *OOH Intermediate Generation in Cu/In2Se3 for Electrochemical H2O2 Production.

Two-electron oxygen reduction reaction (2e- ORR) is a promising method for the synthesis of hydrogen peroxide (H2O2). However, high energy barriers for the generation of key *OOH intermediates hinder the process of 2e- ORR. Herein, we prepared a copper-supported indium selenide catalyst (Cu/In2Se3) to enhance the selectivity and yield of 2e- ORR by employing an electronic metal-support interactions (EMSIs) strategy. EMSIs-induced charge rearrangement between metallic Cu and In2Se3 is conducive to *OOH intermediate generation, promoting H2O2 production. Theoretical investigations reveal that the inclusion of Cu significantly lowers the energy barrier of the 2e- ORR intermediate and impedes the 4e- ORR pathway, thus favoring the formation of H2O2. The concentration of H2O2 produced by Cu/In2Se3 is ~2 times than In2Se3, and Cu/In2Se3 shows promising applications in antibiotic degradation. This research presents a valuable approach for the future utilization of EMSIs in 2e- ORR.

Enhanced molecular oxygen activation via K/O interfacial modification for boosted electrocatalytic degradation over a broad pH range.

Molecular oxygen activation plays an important role in the electrocatalytic degradation of recalcitrant pollutants. And the key lies in the tailoring of electronic structures over catalysts. Herein, carbon nitride with K/O interfacial modification (KOCN) was designed and fabricated for efficient molecular oxygen activation. Theoretical screening results revealed the possible substitution of peripheral N atoms by O atoms and the location of K atoms in the six-fold cavities of g-C3N4 framework. Spectroscopic and experimental results reveal that the existence of K/O promotes charge redistribution over as-prepared catalysts, leading to optimized electronic structures. Therefore, optimized oxygen adsorption was realized over 8 % KOCN, which was further converted into superoxide and singlet oxygen effectively. The rate constant of 8 % KOCN (1.8 × 10-2 min-1) reached 2.2 folds of pristine g-C3N4 (8.1 × 10-3 min-1) counterpart during tetracycline degradation. Moreover, the high electron mobility and excellent structural stability endow the catalyst with remarkable catalytic performance in a broad pH range of 3-11.

The strong metal-support interactions induced electrocatalytic three-electron oxygen reduction to hydroxyl radicals for water treatment.

As a promising environmental remediation technology, the electro-Fenton (EF) process is mainly limited by the two rate-limiting steps, which are H2O2 generation and activation. The electrocatalytic three-electron oxygen reduction reaction (3e- ORR) can directly activate oxygen to hydroxyl radicals (•OH), which is expected to break through the rate-limiting steps of the EF process. However, limited success has been achieved in the design of 3e- ORR electrocatalysts. Herein, we propose Cu/CoSe2/C with the strong metal-support interactions to enhance the 3e- ORR process, exhibiting remarkable reactivity and stability for •OH generation. Both experiment and DFT calculation results reveal that CoSe2 is conducive to the generation of H2O2. Meanwhile, the metallic Cu can enhance the adsorption strength of *H2O2 intermediates and thus promotes the one-electron reduction to •OH. The Cu/CoSe2/C catalyst exhibits the electron-transfer number close to 3.0 during the ORR process, and exhibits the outstanding •OH generation performance, achieving a higher apparent rate constant (6.0 times faster) toward ciprofloxacin compared with its analogy without the SMSI effect. Our work represents that the SMSI effect endows Cu/CoSe2/C high activity and selectivity for •OH generation, providing a unique perspective for the design of a high-efficiency 3e- ORR catalyst.

Landscape of New Nuclease-Containing Antiphage Systems in Escherichia coli and the Counterdefense Roles of Bacteriophage T4 Genome Modifications.

Many phages, such as T4, protect their genomes against the nucleases of bacterial restriction-modification (R-M) and CRISPR-Cas systems through covalent modification of their genomes. Recent studies have revealed many novel nuclease-containing antiphage systems, raising the question of the role of phage genome modifications in countering these systems. Here, by focusing on phage T4 and its host Escherichia coli, we depicted the landscape of the new nuclease-containing systems in E. coli and demonstrated the roles of T4 genome modifications in countering these systems. Our analysis identified at least 17 nuclease-containing defense systems in E. coli, with type III Druantia being the most abundant system, followed by Zorya, Septu, Gabija, AVAST type 4, and qatABCD. Of these, 8 nuclease-containing systems were found to be active against phage T4 infection. During T4 replication in E. coli, 5-hydroxymethyl dCTP is incorporated into the newly synthesized DNA instead of dCTP. The 5-hydroxymethylcytosines (hmCs) are further modified by glycosylation to form glucosyl-5-hydroxymethylcytosine (ghmC). Our data showed that the ghmC modification of the T4 genome abolished the defense activities of Gabija, Shedu, Restriction-like, type III Druantia, and qatABCD systems. The anti-phage T4 activities of the last two systems can also be counteracted by hmC modification. Interestingly, the Restriction-like system specifically restricts phage T4 containing an hmC-modified genome. The ghmC modification cannot abolish the anti-phage T4 activities of Septu, SspBCDE, and mzaABCDE, although it reduces their efficiency. Our study reveals the multidimensional defense strategies of E. coli nuclease-containing systems and the complex roles of T4 genomic modification in countering these defense systems. IMPORTANCE Cleavage of foreign DNA is a well-known mechanism used by bacteria to protect themselves from phage infections. Two well-known bacterial defense systems, R-M and CRISPR-Cas, both contain nucleases that cleave the phage genomes through specific mechanisms. However, phages have evolved different strategies to modify their genomes to prevent cleavage. Recent studies have revealed many novel nuclease-containing antiphage systems from various bacteria and archaea. However, no studies have systematically investigated the nuclease-containing antiphage systems of a specific bacterial species. In addition, the role of phage genome modifications in countering these systems remains unknown. Here, by focusing on phage T4 and its host Escherichia coli, we depicted the landscape of the new nuclease-containing systems in E. coli using all 2,289 genomes available in NCBI. Our studies reveal the multidimensional defense strategies of E. coli nuclease-containing systems and the complex roles of genomic modification of phage T4 in countering these defense systems.

Mitogenome Characterization of Four Conus Species and Comparative Analysis.

Cone snails, as a type of marine organism, have rich species diversity. Traditionally, classifications of cone snails were based mostly on radula, shell, and anatomical characters. Because of these phenotypic features' high population variability and propensity for local adaptation and convergence, identifying species can be difficult and occasionally inaccurate. In addition, mitochondrial genomes contain high phylogenetic information, so complete mitogenomes have been increasingly employed for inferring molecular phylogeny. To enrich the mitogenomic database of cone snails (Caenogastropoda: Conidae), mitogenomes of four Conus species, i.e., C. imperialis (15,505 bp), C. literatus (15,569 bp), C. virgo (15,594 bp), and C. marmoreus (15,579 bp), were characterized and compared. All 4 of these mitogenomes included 13 protein-coding genes, 2 ribosomal RNA genes, 22 tRNA genes, and non-coding regions. All the Protein Codon Genes (PCGs) of both newly sequenced mitogenomes used TAA or TAG as a terminal codon. Most PCGs used conventional start codon ATG, but an alternative initiation codon GTG was detected in a gene (NADH dehydrogenase subunit 4 (nad4)) of C. imperialis. In addition, the phylogenetic relationships were reconstructed among 20 Conus species on the basis of PCGs, COX1, and the complete mitogenome using both Bayesian Inference (BI) and Maximum Likelihood (ML). The phylogenetic results supported that C. litteratus, C. quercinus, and C. virgo were clustered together as a sister group (PP = 1, BS = 99), but they did not support the phylogenetic relation of C. imperialis and C. tribblei (PP = 0.79, BS = 50). In addition, our study established that PCGs and complete mitogenome are the two useful markers for phylogenetic inference of Conus species. These results enriched the data of the cone snail's mitochondrion in the South China Sea and provided a reliable basis for the interpretation of the phylogenetic relationship of the cone snail based on the mitochondrial genome.

Rac1/PAK1 signaling contributes to bone cancer pain by Regulation dendritic spine remodeling in rats.

Bone cancer pain (BCP) is severe chronic pain caused by tumor metastasis to the bones, often resulting in significant skeletal remodeling and fractures. Currently, there is no curative treatment. Therefore, insight into the underlying mechanisms could guide the development of mechanism-based therapeutic strategies for BCP. We speculated that Rac1/PAK1 signaling plays a critical role in the development of BCP. Tumor cells implantation (TCI) into the tibial cavity resulted in bone cancer-associated mechanical allodynia. Golgi staining revealed changes in the excitatory synaptic structure of WDR (Wide-dynamic range) neurons in the spinal cord, including increased postsynaptic density (PSD) length and thickness, and width of the cleft. Behavioral and western blotting test revealed that the development and persistence of pain correlated with Rac1/PAK1 signaling activation in primary sensory neurons. Intrathecal injection of NSC23766, a Rac1 inhibitor, reduced the persistence of BCP as well as reversed the remodeling of dendrites. Therefore, we concluded that activation of the Rac1/PAK1 signaling pathway in the spinal cord plays an important role in the development of BCP through remodeling of dendritic spines. Modulation of the Rac1/PAK1 pathway may be a potential strategy for BCP treatment.

Retention effect and mode of capillary zone on the migration process of LNAPL pollutants based on experimental exploration.

Two-dimensional sand tank experiments were designed to investigate the retention process of the capillary zone during the migration of light non-aqueous phase liquid (LNAPL) pollutants. The fine sand and silt media experiments simulated the LNAPL migration process given a shallow point source leakage scenario. The results indicate that the LNAPL was retained in the capillary zone. A retention factor, based on the ratio of the change in the vertical migration velocity of the LNAPL front with time, was proposed to quantitatively characterize the retention effect. The retention factor and time satisfied the function of σ=A×exp(-kt). And the retention factor increased gradually with time, indicating the enhanced retention effect of capillary zone on the vertical migration of LNAPL. The concentration change rate was then used to investigate the LANPL redistribution process, which had a relationship with time of νc=B×ln(t)+C. The capillary zone could be divided from top to bottom into a weak retention zone (B > 0, vc < 0), a strong retention zone (B < 0), and a barrier zone (B > 0, vc > 0). The retention effect of capillary zone on LNAPL migration gradually strengthened during the vertical migration of LNAPL. In addition, the coefficient B had a relationship with the environmental factors (i.e., EC, pH, and ORP) of B=a×sin(b×α×ß×γ)c and the fitting coefficient R2 of the function was above 0.913 for both media, indicating a strong correlation between the LNAPL redistribution process and the key environmental factors.

Carbon and phosphorus co-doped carbon nitride hollow tube for improved photocatalytic hydrogen evolution.

Graphitic carbon nitride, regarded as a charming conjugated polymer, has been a visible light photocatalyst. Bulk carbon nitride endures the limited light absorption ability, few surface active sites and slow separation of photoinduced charge carriers, leading to the poor catalytic activity. Herein, a new carbon (C) and phosphorus (P) co-doped carbon nitride hollow tube with adjustable optical property (CPCN) was developed by applying melamine and polyacrylic amide as the precursors and phosphoric acid as the P source via a hydrothermal-thermal copolymerization way. The effects of polyacrylic amide content on the morphology and photocatalytic performance were intensively investigated. The special hollow tube favors the improvement of active sites and visible light harvesting ability. Meantime, C and P co-doping results in the narrow band gap and rapid charge transfer, thus enabling an enhanced catalytic activity under visible light irradiation. Particularly, CPCN-50 exhibits a remarkable H2 generation rate of 4485.7 µmol h-1 g-1 under λ > 400 nm, which is higher than pure carbon nitride CN (902.3 µmol h-1 g-1), C doped sample CCN-50 (3741.1 µmol h-1 g-1) and P doped sample CNP (2280.0 µmol h-1 g-1). It implies that C, P co-doping exhibits a synergistic effect on boosting photoinduced charge transfer and hindering the recombination. Moreover, CPCN-50 illustrates a higher H2 generation rate (3024.5 µmol h-1 g-1) than CN (400.8 µmol h-1 g-1) under λ > 420 nm irradiation. This way developed in this work might exhibit utility for synthesizing highly effective photocatalysts for the CO2 reduction, H2 evolution and so on.

Association between blood glucose levels and Glasgow Outcome Score in patients with traumatic brain injury: secondary analysis of a randomized trial.

BACKGROUND: Blood glucose levels that are too high or too low after traumatic brain injury (TBI) negatively affect patient prognosis. This study aimed to demonstrate the relationship between blood glucose levels and the Glasgow Outcome Score (GOS) in TBI patients. METHODS: This study was based on a randomized, dual-center, open-label clinical trial. A total of 208 patients who participated in the randomized controlled trial were followed up for 5 years. Information on the disease, laboratory examination, insulin therapy, and surgery for patients with TBI was collected as candidate variables according to clinical importance. Additionally, data on 5-year and 6-month GOS were collected as primary and secondary outcomes, respectively. For multivariate analysis, a generalized additive model (GAM) was used to investigate relationships between blood glucose levels and GOS. The results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs). We further applied a two- piecewise linear regression model to examine the threshold effect of blood glucose level and GOS. RESULTS: A total of 182 patients were included in the final analysis. Multivariate GAM analysis revealed that a bell-shaped relationship existed between average blood glucose level and 5-year GOS score or 6-month GOS score. The inflection points of the average blood glucose level were 8.81 (95% CI: 7.43-9.48) mmol/L considering 5-year GOS as the outcome and were 8.88 (95% CI 7.43-9.74) mmol/L considering 6-month GOS score as the outcome. The same analysis revealed that there was also a bell relationship between average blood glucose levels and the favorable outcome group (GOS score ≥ 4) at 5 years or 6 months. CONCLUSION: In a population of patients with traumatic brain injury, blood glucose levels were associated with the GOS. There was also a threshold effect between blood glucose levels and the GOS. A blood glucose level that is either too high or too low conveys a poor prognosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02161055 . Registered on 11 June 2014.

Large-scale defect-rich iron/nitrogen co-doped graphene-based materials as the excellent bifunctional electrocatalyst for liquid and flexible all-solid-state zinc-air batteries.

Defect-engineering in transition-metal-doped carbon-based catalyst plays an essential role for improving the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) performance. Herein, we report a ball-milling induced defect assisted with ZnCl2 strategy for fabricating defect-rich iron/nitrogen co-doped graphene-based materials (Fe-N-G). The substantial mechanical shear forces and the constant corrosion to the carbon matrix by ZnCl2 lead to the creation of abundant defects in graphene-based materials, which facilitates doping for heteroatoms. The defect-rich Fe-N-G catalyst with abundant Fe-Nx active sites displays excellent ORR performance. For OER, the over potential for Fe-N-G outperforms that of RuO2 in 1 M KOH at 10 mA cm-2. The Density Functional Theory calculations unravel that the impressive OER performance is attributable to the introduction of abundant defects. Additionally, the liquid and all-solid-state zinc-air batteries equipped with the prepared material as the air cathode demonstrate high power density, high specific capacity, and long charge-discharge stability. This work offers a practical method for manufacturing high-performance electrocatalysts for environmental and energy-related fields.

Monitoring the Landscape Pattern and Characteristics of Non-Point Source Pollution in a Mountainous River Basin.

This study aimed to assess the relationship between the landscape patterns and non-point source (NPS) pollution distribution in Qixia County, China. The sub-basin classification was conducted based on a digital elevation model and Landsat8 satellite images. Water samples were collected from each sub-basin, andtheir water quality during the wet and dry seasons was estimated. The correlation between the landscape indices and water pollution indicators was determined by Pearson analysis. The location-weighted landscape contrast index (LWLCI) was calculated based on the "source-sink" theory. Qixia was further divided into five sections based on the LWLCI score to illustrate the potential risk of NPS pollution. The results showed that the water quality in Qixia County was generally good. Cultivated land, orchards, construction areas, and unused land were positively correlated with the water pollution index and weredesignated as the "source" landscape categories, while forests, grasslands, and water bodies, which were negatively correlated with water pollution, were the "sink" landscapes; the LWCI was high in 36.94% of the study area. In these areas, measures such as increasing vegetation buffer zones are necessary to decrease the sediment and nutrient loads carried by precipitation.

Engineering T4 Bacteriophage for In Vivo Display by Type V CRISPR-Cas Genome Editing.

Bacteriophage T4 has enormous potential for biomedical applications due to its large size, capsid architecture, and high payload capability for protein and DNA delivery. However, it is not very easy to genetically engineer its genome heavily modified by cytosine hydroxymethylation and glucosylation. The glucosyl hydroxymethyl cytosine (ghmC) genome of phage is completely resistant to most restriction endonucleases and exhibits various degrees of resistance to CRISPR-Cas systems. Here, we found that the type V CRISPR-Cas12a system, which shows efficient cleavage of ghmC-modified genome when compared to the type II CRISPR-Cas9 system, can be synergistically employed to generate recombinant T4 phages. Focused on surface display, we analyzed the ability of phage T4 outer capsid proteins Hoc (highly antigenic outer capsid protein) and Soc (small outer capsid protein) to tether, in vivo, foreign peptides and proteins to T4 capsid. Our data show that while these could be successfully expressed and displayed during the phage infection, shorter peptides are present at a much higher copy number than full-length proteins. However, the copy number of the latter could be elevated by driving the expression of the transgene using the strong T7 RNA polymerase expression system. This CRISPR-inspired approach has the potential to expand the application of phages to various basic and translational research projects.

Covalent Modifications of the Bacteriophage Genome Confer a Degree of Resistance to Bacterial CRISPR Systems.

The interplay between defense and counterdefense systems of bacteria and bacteriophages has been driving the evolution of both organisms, leading to their great genetic diversity. Restriction-modification systems are well-studied defense mechanisms of bacteria, while phages have evolved covalent modifications as a counterdefense mechanism to protect their genomes against restriction. Here, we present evidence that these genome modifications might also have been selected to counter, broadly, the CRISPR-Cas systems, an adaptive bacterial defense mechanism. We found that the phage T4 genome modified by cytosine hydroxymethylation and glucosylation (ghmC) exhibits various degrees of resistance to the type V CRISPR-Cas12a system, producing orders of magnitude more progeny than the T4(C) mutant, which contains unmodified cytosines. Furthermore, the progeny accumulated CRISPR escape mutations, allowing rapid evolution of mutant phages under CRISPR pressure. A synergistic effect on phage restriction was observed when two CRISPR-Cas12a complexes were targeted to independent sites on the phage genome, another potential countermechanism by bacteria to more effectively defend themselves against modified phages. These studies suggest that the defense-counterdefense mechanisms exhibited by bacteria and phages, while affording protection against one another, also provide evolutionary benefits for both.IMPORTANCE Restriction-modification (R-M) and CRISPR-Cas systems are two well-known defense mechanisms of bacteria. Both recognize and cleave phage DNA at specific sites while protecting their own genomes. It is well accepted that T4 and other phages have evolved counterdefense mechanisms to protect their genomes from R-M cleavage by covalent modifications, such as the hydroxymethylation and glucosylation of cytosine. However, it is unclear whether such genome modifications also provide broad protection against the CRISPR-Cas systems. Our results suggest that genome modifications indeed afford resistance against CRISPR systems. However, the resistance is not complete, and it is also variable, allowing rapid evolution of mutant phages that escape CRISPR pressure. Bacteria in turn could target more than one site on the phage genome to more effectively restrict the infection of ghmC-modified phage. Such defense-counterdefense strategies seem to confer survival advantages to both the organisms, one of the possible reasons for their great diversity.

Highly Exposed Active Sites of Fe/N Co-doped Defect-rich Graphene as an Efficient Electrocatalyst for Oxygen Reduction Reaction.

A defect-rich interconnected hierarchical three-dimensional Fe and N co-doped graphene has been prepared by a facile synthesis with poly (2,5-benzimidazole) (ABPBI) as nitrogen and carbon sources and CaCO3 as the template. ABPBI possesses abundant nitrogen, and pyrolysis of ABPBI is helpful to form graphene structure. CaCO3 and its decomposition products CO2 can promote the formation of interconnected hierarchical porous three-dimensional graphene, which possesses more defects and exposed active sites. Benefiting from the defective catalysis mechanism, rich defect catalysts are applied as electrode materials to enhance the catalytic performance for oxygen reduction reaction (ORR). Electrochemically, the half-wave potential (E1/2 ) of Fe-3D-NG#800 is 0.84 V (vs. RHE), and the accelerated durability tests shows the E1/2 of Fe-3D-NG#800 shifted by a 21 mV drop after cyclic voltammetry scanning for 5000 cycles. Therefore, Fe-3D-NG#800 has excellent activity and durability than 20 wt % Pt/C.

Dexmedetomidine inhibits the NF-κB pathway and NLRP3 inflammasome to attenuate papain-induced osteoarthritis in rats.

Context: Dexmedetomidine (Dex) has been reported to have an anti-inflammatory effect. However, its role on osteoarthritis (OA) has not been explored. Objective: This study investigates the effect of Dex on OA rat model induced by papain. Materials and methods: The OA Wistar rat model was induced by intraluminal injection of 20 mL of papain mixed solution (4% papain 0.2 mL mixed with 0.03 mol L-1 l-cysteine 0.1 mL) into the right knee joint. Two weeks after papain injection, OA rats were treated by intra-articular injection of Dex (5, 10, or 20 µg kg-1) into the right knee (once a day, continuously for 4 weeks). Articular cartilage tissue was obtained after Dex treatment was completed. Results: The gait behavior scores (2.83 ± 0.49), PWMT (15.2 ± 1.78) and PTWL (14.81 ± 0.92) in H-DEX group were higher than that of OA group, while Mankin score (5.5 ± 0.81) was decreased (p < 0.05). Compared with the OA group, the IL-1ß (153.11 ± 16.05 pg mg-1), IL-18 (3.71 ± 0.7 pg mg-1), IL-6 (14.15 ± 1.94 pg/mg) and TNF-α (40.45 ± 10.28 pg mg-1) levels in H-DEX group were decreased (p < 0.05). MMP-13, NLRP3, and caspase-1 p10 expression in Dex groups were significantly lower than that of OA group (p < 0.05), while collagen II was increased (p < 0.05). p65 in the nucleus of Dex groups was significantly down-regulated than that of OA group (p < 0.05). Discussion and Conclusions: Dex can improve pain symptoms and cartilage tissue damage of OA rats, which may be related to its inhibition of the activation of NF-κB and NLRP3 inflammasome.

Electrical peripheral nerve stimulation relieves bone cancer pain by inducing Arc protein expression in the spinal cord dorsal horn.

OBJECTIVE: The analgesic effect on chronic pain of peripheral nerve stimulation (PNS) has been proven, but its underlying mechanism remains unknown. Therefore, this study aimed to assess the analgesic effect of PNS on bone cancer pain in a rat model and to explore the underlying mechanism. MATERIALS AND METHODS: PNS on sciatic nerves with bipolar electrode was performed in both naïve and bone cancer pain model rats. Then, the protein levels of activity-regulated cytoskeleton-associated protein (Arc), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor 1 (GluA1), and phosphate N-methyl-d-aspartic acid-type glutamate receptor subunit 2B (pGluNR2B) in spinal cord were evaluated by immunohistochemistry and Western blotting. Thermal paw withdraw latency and mechanical paw withdraw threshold were used to estimate the analgesic effect of PNS on bone cancer pain. Intrathecal administration of Arc shRNA was used to inhibit Arc expression in the spinal cord. RESULTS: PNS at 60 and 120 Hz for 20 min overtly induced Arc expression in the spinal cord, increased thermal pain thresholds in naïve rats, and relieved bone cancer pain; meanwhile, 10 Hz PNS did not achieve those results. In addition, PNS at 60 and 120 Hz also reduced the expression of GluA1, but not pGluNR2B, in the spinal cord. Finally, the anti-nociceptive effect and GluA1 downregulation induced by PNS were inhibited by intrathecal administration of Arc shRNA. CONCLUSION: PNS (60 Hz, 0.3 mA) can relieve bone-cancer-induced allodynia and hyperalgesia by upregulating Arc protein expression and then by decreasing GluA1 transcription in the spinal cord dorsal horn.

Hedgehog signaling contributes to bone cancer pain by regulating sensory neuron excitability in rats.

Treating bone cancer pain continues to be a clinical challenge and underlying mechanisms of bone cancer pain remain elusive. Here, we reported that sonic hedgehog signaling plays a critical role in the development of bone cancer pain. Tibia bone cavity tumor cell implantation produces bone cancer-related mechanical allodynia, thermal hyperalgesia, and spontaneous and movement-evoked pain behaviors. Production and persistence of these pain behaviors are well correlated with tumor cell implantation-induced up-regulation and activation of sonic hedgehog signaling in primary sensory neurons and spinal cord. Spinal administration of sonic hedgehog signaling inhibitor cyclopamine prevents and reverses the induction and persistence of bone cancer pain without affecting normal pain sensitivity. Inhibiting sonic hedgehog signaling activation with cyclopamine, in vivo or in vitro, greatly suppresses tumor cell implantation-induced increase of intracellular Ca2+ and hyperexcitability of the sensory neurons and also the activation of GluN2B receptor and the subsequent Ca2+-dependent signals CaMKII and CREB in dorsal root ganglion and the spinal cord. These findings show a critical mechanism underlying the pathogenesis of bone cancer pain and suggest that targeting sonic hedgehog signaling may be an effective approach for treating bone cancer pain.

Safety and efficacy of the oblique-axis plane in ultrasound-guided internal jugular vein puncture: A meta-analysis.

Objective This meta-analysis was performed to evaluate the safety and efficacy of the oblique-axis plane in ultrasound-guided internal jugular vein puncture. Methods We searched Embase, PubMed, the Cochrane Library, Web of Science, and China National Knowledge Infrastructure for relevant randomized clinical trials comparing the oblique axis with the short axis in ultrasound-guided internal jugular vein puncture. Results Five randomized clinical trials were included in this meta-analysis. The pooled meta-analysis showed that the incidence of arterial puncture in the oblique-axis group was significantly lower than that in the short-axis group. No significant difference was found in the first-pass success rate between the oblique-axis group and short-axis group. Additionally, there were no significant differences in the puncture success rate or number of attempts required between the two groups. Conclusion Ultrasound-guided internal jugular vein puncture using the oblique-axis plane reduced the risk of arterial puncture, but no difference was found in the first-pass success rate, puncture success rate, or number of attempts required.

Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression.

PURPOSE: Preventing opioid-induced hyperalgesia and tolerance continues to be a major clinical challenge, and the underlying mechanisms of hyperalgesia and tolerance remain elusive. Here, we investigated the role of sonic hedgehog (Shh) signaling in opioid-induced hyperalgesia and tolerance. METHODS: Shh signaling expression, behavioral changes, and neurochemical alterations induced by morphine were analyzed in male adult CD-1 mice with repeated administration of morphine. To investigate the contribution of Shh to morphine-induced hyperalgesia (MIH) and tolerance, Shh signaling inhibitor cyclopamine and Shh small interfering RNA (siRNA) were used. To explore the mechanisms of Shh signaling in MIH and tolerance, brain-derived neurotrophic factor (BDNF) inhibitor K252 and anti-BDNF antibody were used. RESULTS: Repeated administration of morphine produced obvious hyperalgesia and tolerance. The behavioral changes were correlated with the upregulation and activation of morphine treatment-induced Shh signaling. Pharmacologic and genetic inhibition of Shh signaling significantly delayed the generation of MIH and tolerance and associated neurochemical changes. Chronic morphine administration also induced upregulation of BDNF. Inhibiting BDNF effectively delayed the generation of MIH and tolerance. The upregulation of BDNF induced by morphine was significantly suppressed by inhibiting Shh signaling. In naïve mice, exogenous activation of Shh signaling caused a rapid increase of BDNF expression, as well as thermal hyperalgesia. Inhibiting BDNF significantly suppressed smoothened agonist-induced hyperalgesia. CONCLUSION: These findings suggest that Shh signaling may be a critical mediator for MIH and tolerance by regulating BDNF expression. Inhibiting Shh signaling, especially during the early phase, may effectively delay or suppress MIH and tolerance.