LncRNA CamK-A Regulates Ca2+-Signaling-Mediated Tumor Microenvironment Remodeling.

Cancer cells entail metabolic adaptation and microenvironmental remodeling to survive and progress. Both calcium (Ca2+) flux and Ca2+-dependent signaling play a crucial role in this process, although the underlying mechanism has yet to be elucidated. Through RNA screening, we identified one long noncoding RNA (lncRNA) named CamK-A (lncRNA for calcium-dependent kinase activation) in tumorigenesis. CamK-A is highly expressed in multiple human cancers and involved in cancer microenvironment remodeling via activation of Ca2+-triggered signaling. Mechanistically, CamK-A activates Ca2+/calmodulin-dependent kinase PNCK, which in turn phosphorylates IκBα and triggers calcium-dependent nuclear factor κB (NF-κB) activation. This regulation results in the tumor microenvironment remodeling, including macrophage recruitment, angiogenesis, and tumor progression. Notably, our human-patient-derived xenograft (PDX) model studies demonstrate that targeting CamK-A robustly impaired cancer development. Clinically, CamK-A expression coordinates with the activation of CaMK-NF-κB axis, and its high expression indicates poor patient survival rate, suggesting its role as a potential biomarker and therapeutic target.

Numerical study of the upwelling and downwelling effects of artificial reefs along tidal cycles in the Pearl River Estuary.

Artificial reefs (ARs) are a preferred option for managers due to their distinctive hydrodynamic properties, which support a highly productive local ecosystem. However, the hydrodynamics characteristics of ARs in natural marine environments have not been conducted. Being the first to explore the spatiotemporal characteristic of flow fields around ARs along tidal cycles in marine environments, this study redefined the upwelling and downwelling of ARs, based on natural vertical velocities, and separated the upwelling into co-direction upwelling and re-direction upwelling, and the downwelling into co-direction downwelling and re-direction downwelling. This study simulated the flow field in the Wanshan ARs area of the Pearl River Estuary along the tidal cycles using the MIKE3-FM. Numerical simulations revealed that (1) co-direction upwelling and co-direction downwelling were the dominant components of the vertical flow field effects of ARs; (2) the areas sum of upwelling and downwelling were largest in the medium water column, with about 1.6 and 1.03 times as large as the bottom and surface water column, respectively, while the fluxes sum of the upwelling and downwelling were largest in bottom water column, with approximately 1.3 and 2.2 times larger than those in the middle and surface water columns; (3) the area and volume of the upwelling and downwelling gradually decreased along neap-spring tide, exhibited significantly negative correlations with current speeds; while the upwelling flux and downwelling flux gradually increased along neap-spring tide; exhibited a significantly positive correlation with current speed; (4) the effects of tide to upwelling and downwelling of AR are forced by the northward velocity of current speed, the net flux of upwelling and downwelling showed a significant positive correlation with the northward velocity of current speed (r = 0.94). These results could provide a reference for assessing the flow field effect of ARs and a guide for the configuration and management of ARs.

Smoking and alcohol consumption with the risk of 11 common otolaryngological diseases: a bidirectional Mendelian randomization.

PURPOSE: In this study, a bidirectional mendelian randomization was applied to evaluate the association of smoking and alcohol consumption with 11 otolaryngological diseases. METHODS: A total of 85,22,34 and 7 single nucleotide polymorphisms were used as instrumental variables for smoking initiation, cigarettes per day, alcoholic drinks per week and alcohol consumption, respectively. Genetic associations with 11 common otolaryngological diseases were obtained from the UK Biobank and FinnGen dataset. IVW, weighted median, MR-Egger, MR-PRESSO and leave-one-out method were used in this analysis. RESULTS: Smoking initiation increased the risk of vocal cord and larynx diseases (OR 1.002; 95% CI 1.001-1.004; P = 4 × 10-4), head and neck cancer (OR 1.001; 95% CI 0.999-1.003; P = 0.027), thyroid cancer (OR 1.538; 95% CI 1.006-2.351; P = 0.047) and sleep apnoea (OR 1.286; 95% CI 1.099-1.506; P = 0.002). Cigarettes per day was associated with chronic sinusitis (OR 1.152; 95% CI 1.002-1.324; P = 0.046), chronic rhinitis and pharyngitis (OR 1.200; 95% CI 1.033-1.393; P = 0.017), vocal cord and larynx diseases (OR 1.001; 95% CI 0.999-1.002; P = 0.021) and head and neck cancer (OR 1.001; 95% CI 0.999-1.003; P = 0.017). Alcoholic drinks per week only was significantly associated with the risk of head and neck cancer (OR 1.003; 95% CI 1.001-1.006; P = 0.014). However, there was no evidence to support that genetically predicted alcohol consumption increased the risk of otolaryngological diseases. Reverse MR also did not find outcomes effect on exposures. CONCLUSION: This study shows that smoking and heavy alcohol consumption promote the occurrence of some otolaryngological diseases indicating that lifestyle modification might be beneficial in preventing otolaryngological diseases.

Zika virus tropism during early infection of the testicular interstitium and its role in viral pathogenesis in the testes.

Sexual transmission and persistence of Zika virus (ZIKV) in the testes pose new challenges for controlling virus outbreaks and developing live-attenuated vaccines. It has been shown that testicular infection of ZIKV is initiated in the testicular interstitium, followed by spread of the virus in the seminiferous tubules. This leads to testicular damage and/or viral dissemination into the epididymis and eventually into semen. However, it remains unknown which cell types are targeted by ZIKV in the testicular interstitium, and what is the specific order of infectious events leading to ZIKV invasion of the seminiferous tubules. Here, we demonstrate that interstitial leukocytes expressing mir-511-3p microRNA are the initial targets of ZIKV in the testes, and infection of mir-511-3p-expressing cells in the testicular interstitium is necessary for downstream infection of the seminiferous tubules. Mir-511-3p is expressed concurrently with CD206, a marker of lineage 2 (M2) macrophages and monocyte derived dendritic cells (moDCs). Selective restriction of ZIKV infection of CD206-expressing M2 macrophages/moDCs results in the attenuation of macrophage-associated inflammatory responses in vivo and prevents the disruption of the Sertoli cell barrier in vitro. Finally, we show that targeting of viral genome for mir-511-3p significantly attenuates early ZIKV replication not only in the testes, but also in many peripheral organs, including spleen, epididymis, and pancreas. This incriminates M2 macrophages/moDCs as important targets for visceral ZIKV replication following hematogenous dissemination of the virus from the site of infection.

LncRNA wires up Hippo and Hedgehog signaling to reprogramme glucose metabolism.

The Hippo pathway plays essential roles in organ size control and cancer prevention via restricting its downstream effector, Yes-associated protein (YAP). Previous studies have revealed an oncogenic function of YAP in reprogramming glucose metabolism, while the underlying mechanism remains to be fully clarified. Accumulating evidence suggests long noncoding RNAs (lncRNAs) as attractive therapeutic targets, given their roles in modulating various cancer-related signaling pathways. In this study, we report that lncRNA breast cancer anti-estrogen resistance 4 (BCAR4) is required for YAP-dependent glycolysis. Mechanistically, YAP promotes the expression of BCAR4, which subsequently coordinates the Hedgehog signaling to enhance the transcription of glycolysis activators HK2 and PFKFB3. Therapeutic delivery of locked nucleic acids (LNAs) targeting BCAR4 attenuated YAP-dependent glycolysis and tumor growth. The expression levels of BCAR4 and YAP are positively correlated in tissue samples from breast cancer patients, where high expression of both BCAR4 and YAP is associated with poor patient survival outcome. Taken together, our study not only reveals the mechanism by which YAP reprograms glucose metabolism, but also highlights the therapeutic potential of targeting YAP-BCAR4-glycolysis axis for breast cancer treatment.

Patterning a Superhydrophobic Area on a Facile Fabricated Superhydrophilic Layer Based on an Inkjet-Printed Water-Soluble Polymer Template.

An elaborated surface with a superhydrophilic area and a superhydrophobic area was fabricated by inkjet printing a water-soluble polymer template on a superhydrophilic layer. Titanate was used to generate the superhydrophilic layer with an in situ reaction. A water-soluble polymer template was inkjet printed on the facile fabricated superhydrophilic layer. Superhydrophobic treatment was carried out on the inkjet-printed surface with perfluorinated molecules. A superhydrophilic-superhydrophobic patterned surface (SSPS) was obtained by washing out the water-soluble polymer template. Various patterns of SSPS were fabricated with the different water-soluble polymer templates. Then, adhesion and deposition of water droplets were studied on the SSPS with the different wetting abilities on the surface. Meanwhile, a microreaction with a microfluidic chip was realized on the SSPS. In this work, systematic research on fabricating an SSPS based on a facile fabricated superhydrophilic layer with an inkjet-printed water-soluble polymer template is presented. It will have great potential for patterning materials, fabricating devices, and researching interfaces, such as microdroplet self-removal, analyte enrichment, and liquid-liquid interface reaction.

cGAMP inhibits tumor growth in colorectal cancer metastasis through the STING/STAT3 axis in a zebrafish xenograft model.

The leading cause of mortality due to colorectal cancer (CRC) is highly associated with the development of liver metastases. Recently, we described cGAMP that is closely related to the metastatic state wherein the progress of metastatic tumors is associated with favorable outcomes in a zebrafish xenograft model. cGAMP was administered and the expression levels of type-I interferons were induced amongst tumor tissues to illuminate the overall measure of the induced STING/STAT3 axis in colorectal liver metastases. Furthermore, cGAMP-STING dependent STAT3 activation resulted in the inhibition of tumor cell proliferation, viability, and invasion in vitro. The subtotal reduction in tumor growth attributed to a large number of infiltrating inflammatory cells in vivo. We showed that cGAMP inhibited migration through angiogenesis by up-regulating IL-2, TNF-α, and IFN-γ, whereas STAT3 down-regulation inhibited CXCL8, BCL-2, and VEGFA expression. The importance of cGAMP in inhibiting the invasion front of CRC confirmed that the cGAMP dependent activation of STING/STAT3 axis played a key role in the inhibition of tumor progression.

Effect of Sustained Hypoxia on Autophagy of Genioglossus Muscle-Derived Stem Cells.

BACKGROUND Previous studies have demonstrated that sustained hypoxia in people with obstructive sleep apnea (OSA) impairs upper airway muscle activity, but the underlying mechanism remains poorly understood. As autophagy acts as an important regulator under hypoxia stress, we performed an in vitro investigation of the effects of sustained hypoxia on autophagy of genioglossus muscle-derived stem cells (GG MDSC), an important component of the upper airway muscle. MATERIAL AND METHODS Genioglossus MDSCs were obtained from Sprague-Dawley (SD) rats and identified by using immunofluorescence staining for CD34, Sca-1, and desmin. GG MDSCs were incubated under normoxic or sustained hypoxic conditions for different periods of time. Western blotting was used to detect LC3 and Beclin 1, which are 2 important proteins in autophagy flux, and autophagolysosomes accumulation was observed by transmission electron microscopy (TEM). The mRNA and protein levels of HIF-1α and BNIP3 were evaluated by RT-PCR and Western blot analysis, respectively. RESULTS Our study shows that sustained hypoxia promotes the expression of LC3BII and Beclin 1 in GG MDSCs in a time-dependent manner. TEM showed an increased number of autophagolysosomes in GG MDSCs under sustained hypoxia for 12 and 24 h. In addition, hypoxia activated the HIF-1α/BNIP3 signal pathway both at protein levels (shown by Western blot) and at mRNA levels (shown by RT-PCR). CONCLUSIONS Our study shows that sustained hypoxia promotes autophagy in GG MDSCs, and the HIF-1a/BNIP3 signal pathway was involved in this process.

Kissing-loop interaction between 5' and 3' ends of tick-borne Langat virus genome 'bridges the gap' between mosquito- and tick-borne flaviviruses in mechanisms of viral RNA cyclization: applications for virus attenuation and vaccine development.

Insertion of microRNA target sequences into the flavivirus genome results in selective tissue-specific attenuation and host-range restriction of live attenuated vaccine viruses. However, previous strategies for miRNA-targeting did not incorporate a mechanism to prevent target elimination under miRNA-mediated selective pressure, restricting their use in vaccine development. To overcome this limitation, we developed a new approach for miRNA-targeting of tick-borne flavivirus (Langat virus, LGTV) in the duplicated capsid gene region (DCGR). Genetic stability of viruses with DCGR was ensured by the presence of multiple cis-acting elements within the N-terminal capsid coding region, including the stem-loop structure (5'SL6) at the 3' end of the promoter. We found that the 5'SL6 functions as a structural scaffold for the conserved hexanucleotide motif at its tip and engages in a complementary interaction with the region present in the 3' NCR to enhance viral RNA replication. The resulting kissing-loop interaction, common in tick-borne flaviviruses, supports a single pair of cyclization elements (CYC) and functions as a homolog of the second pair of CYC that is present in the majority of mosquito-borne flaviviruses. Placing miRNA targets into the DCGR results in superior attenuation of LGTV in the CNS and does not interfere with development of protective immunity in immunized mice.

Dual miRNA targeting restricts host range and attenuates neurovirulence of flaviviruses.

Mosquito-borne flaviviruses are among the most significant arboviral pathogens worldwide. Vaccinations and mosquito population control programs remain the most reliable means for flavivirus disease prevention, and live attenuated viruses remain one of the most attractive flavivirus vaccine platforms. Some live attenuated viruses are capable of infecting principle mosquito vectors, as demonstrated in the laboratory, which in combination with their intrinsic genetic instability could potentially lead to a vaccine virus reversion back to wild-type in nature, followed by introduction and dissemination of potentially dangerous viral strains into new geographic locations. To mitigate this risk we developed a microRNA-targeting approach that selectively restricts replication of flavivirus in the mosquito host. Introduction of sequences complementary to a mosquito-specific mir-184 and mir-275 miRNAs individually or in combination into the 3'NCR and/or ORF region resulted in selective restriction of dengue type 4 virus (DEN4) replication in mosquito cell lines and adult Aedes mosquitos. Moreover a combined targeting of DEN4 genome with mosquito-specific and vertebrate CNS-specific mir-124 miRNA can silence viral replication in two evolutionally distant biological systems: mosquitoes and mouse brains. Thus, this approach can reinforce the safety of newly developed or existing vaccines for use in humans and could provide an additional level of biosafety for laboratories using viruses with altered pathogenic or transmissibility characteristics.

Low Expression of CAPON in Glioma Contributes to Cell Proliferation via the Akt Signaling Pathway.

CAPON is an adapter protein for nitric oxide synthase 1 (NOS1). CAPON has two isoforms in the human brain: CAPON-L (long form of CAPON) and CAPON-S (short form of CAPON). Recent studies have indicated the involvement of CAPON in tumorigenesis beyond its classical role in NOS1 activity regulation. In this study, we found that the protein levels of CAPON-S, but not than CAPON-L, were significantly decreased in glioma tissues. Therefore, we established lentivirus-mediated stable cell lines with CAPON-S overexpression or down-regulation, and investigated the role of CAPON-S in the proliferation of glioma cells by using CCK8, EdU, and flow cytometry assays. Overexpression of CAPON-S reduced the cell variability and the percentage of EdU-positive cells, and arrested the cells in the G1 phase in glioma cells. Silencing of CAPON by short-hairpin RNA showed the opposite effects. Furthermore, an intracellular signaling array revealed that overexpression of CAPON-S resulted in a remarkable reduction in the phosphorylation of Akt and S6 ribosomal protein in glioma cells, which was further confirmed by Western blot. These findings suggest that CAPON may function as a tumor suppressor in human brain glioma and that the inactivation of the Akt signaling pathway caused by CAPON-S overexpression may provide insight into the underlying mechanism of CAPON in glioma cell proliferation.

Effects of sex and COMT genotype on environmentally modulated cognitive control in mice.

Cognitive functioning differs between males and females, likely in part related to genetic dimorphisms. An example of a common genetic variation reported to have sexually dimorphic effects on cognition and temperament in humans is the Val/Met polymorphism in catechol-O-methyltransferase (COMT). We tested male and female wild-type mice ((+/+)) and their COMT knockout littermates ((+/-) and (-/-)) in the five-choice serial reaction time task (5CSRTT) to investigate the effects of sex, COMT genotype, and their interactions with environmental manipulations of cognitive functions such as attention, impulsivity, compulsivity, motivation, and rule-reversal learning. No sex- or COMT-dependent differences were present in the basic acquisition of the five-choice serial reaction time task. In contrast, specific environmental manipulations revealed a variety of sex- and COMT-dependent effects. Following an experimental change to trigger impulsive responding, the sexes showed similar increases in impulsiveness, but males eventually habituated whereas females did not. Moreover, COMT knockout mice were more impulsive compared with wild-type littermates. Manipulations involving mild stress adversely affected cognitive performance in males, and particularly COMT knockout males, but not in females. In contrast, following amphetamine treatment, subtle sex by genotype and sex by treatment interactions emerged primarily limited to compulsive behavior. After repeated testing, female mice showed improved performance, working harder and eventually outperforming males. Finally, removing the food-restriction condition enhanced sex and COMT differences, revealing that overall, females outperform males and COMT knockout males outperform their wild-type littermates. These findings illuminate complex sex- and COMT-related effects and their interactions with environmental factors to influence specific executive cognitive domains.

Constructing a high-density linkage map for Gossypium hirsutum × Gossypium barbadense and identifying QTLs for lint percentage.

To introgress the good fiber quality and yield from Gossypium barbadense into a commercial Upland cotton variety, a high-density simple sequence repeat (SSR) genetic linkage map was developed from a BC1 F1 population of Gossypium hirsutum × Gossypium barbadense. The map comprised 2,292 loci and covered 5115.16 centiMorgan (cM) of the cotton AD genome, with an average marker interval of 2.23 cM. Of the marker order for 1,577 common loci on this new map, 90.36% agrees well with the marker order on the D genome sequence genetic map. Compared with five published high-density SSR genetic maps, 53.14% of marker loci were newly discovered in this map. Twenty-six quantitative trait loci (QTLs) for lint percentage (LP) were identified on nine chromosomes. Nine stable or common QTLs could be used for marker-assisted selection. Fifty percent of the QTLs were from G. barbadense and increased LP by 1.07%-2.41%. These results indicated that the map could be used for screening chromosome substitution segments from G. barbadense in the Upland cotton background, identifying QTLs or genes from G. barbadense, and further developing the gene pyramiding effect for improving fiber yield and quality.

The mood stabilizer lithium potentiates the antidepressant-like effects and ameliorates oxidative stress induced by acute ketamine in a mouse model of stress.

BACKGROUND: Evidence suggests that mammalian target of rapamycin activation mediates ketamine's rapid but transient antidepressant effects and that glycogen synthase kinase-3ß inhibits this pathway. However, ketamine has associated psychotomimetic effects and a high risk of abuse. The mood stabilizer lithium is a glycogen synthase kinase-3 inhibitor with strong antisuicidal properties. Here, we used a mouse stress model to investigate whether adjunct lithium treatment would potentiate ketamine's antidepressant-like effects. METHODS: Mice received chronic restraint stress and long-term pre- or postketamine lithium treatment in drinking water. The effects of lithium on ketamine-induced antidepressant-like effects, activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways, oxidative stress, and dendritic spine density in the brain of mice were investigated. RESULTS: Subtherapeutic (600 mg/L) lithium-pretreated mice exhibited an antidepressant-like response to an ineffective ketamine (2.5 mg/kg, intraperitoneally) challenge in the forced swim test. Both the antidepressant-like effects and restoration of dendritic spine density in the medial prefrontal cortex of stressed mice induced by a single ketamine (50 mg/kg) injection were sustained by postketamine treatment with 1200 mg/L of lithium for at least 2 weeks. These benefits of lithium treatments were associated with activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways in the prefrontal cortex. Acute ketamine (50 mg/kg) injection also significantly increased lipid peroxidation, catalase activity, and oxidized glutathione levels in stressed mice. Notably, these oxidative stress markers were completely abolished by pretreatment with 1200 mg/L of lithium. CONCLUSIONS: Our results suggest a novel therapeutic strategy and justify the use of lithium in patients who benefit from ketamine.

Internet follow-up can improve the compliance of sublingual immunotherapy in children with allergic rhinitis: a retrospective cohort study.

Background: Sublingual immunotherapy (SLIT) is an effective approach for treating allergic rhinitis in children. Although the curative effect of SLIT is significant, the compliance of patients is poor because of the long treatment time. How to improve patients' compliance with SLIT is an important clinical problem faced by otolaryngology clinicians. At present, there are few studies on SLIT compliance. The present study aimed to analyze the related factors affecting SLIT compliance in children with allergic rhinitis (AR). Methods: In total, 153 patients with AR who received SLIT were selected as the study objects. Seventeen patients were excluded from this study.The patients' demographic, follow-up methods, complications efficacy, compliance data, etc. were collected, and all patients were followed-up regularly. Patients were considered to have poor compliance when they stop taking medication of SLIT. Univariate and multivariable regression analyses were performed to analyze the independent factors influencing SLIT compliance. The odds ratios (ORs) and 95% confidence intervals (CIs) were computed by logistic regression. Results: A total of 136 patients were enrolled in this study. The baseline clinical factors of the two groups of follow-up methods were balanced and comparable. Among these, 35 patients (25.7%) ceased SLIT. There was a significant difference in compliance between the Internet follow-up group and the traditional follow-up group (P<0.001). Univariate logistic regression analysis showed that SLIT compliance was significantly related to residence (P<0.001), the caregiver's education level (P<0.001), follow-up methods (P<0.001), and whether the patient also had asthma (P<0.002). In the multivariate regression analysis, it was found that the follow-up methods (OR =7.60, 95% CI: 2.20-26.21, P=0.001) and caregiver's education level (OR =8.54, 95% CI: 3.04-23.95, P<0.001) were independent factors influencing SLIT compliance after adjusting for residence and whether the patient also had asthma. Conclusions: Our study found that the follow-up methods and the education level of caregivers were independent factors affecting SLIT compliance in children with AR. This study suggested that we should use the Internet follow-up method for children treated with SLIT in the future, and provides a basis for how to improve the compliance of SLIT in children with AR.

Serum vitamin D3 deficiency can affect the efficacy of sublingual immunotherapy in children with allergic rhinitis: a retrospective cohort study.

Background: Sublingual immunotherapy (SLIT) is effective and convenient for many allergic patients but it is still ineffective for many children with allergic rhinitis (AR). In previous studies, most of the patients with poor efficacy of SLIT used the method of individualized adjustment of drug dosage. Currently, there are few reports on the relationship between serum vitamin D3 level and the efficacy of SLIT. Methods: In this study, 153 patients with AR who received SLIT were selected as the study objects. All patients collected serum for vitamin D3 test before treatment. The clinical characteristics of the patients were collected, and all patients were regularly followed up for at least 6 months. The improvement rates were assessed according to the combined symptom medication score (CSMS). A receiver operating characteristic (ROC) curve was drawn, and the optimal cut-off point was determined according to the Youden index. Univariate and multivariate logistic regression were used to analyze the relationship between serum vitamin D3 and SLIT efficacy. The odds ratios (ORs) and 95% confidence intervals (CIs) were computed by logistic regression. Results: Of 153 AR patients, 101 patients entered the final statistical analysis. According to CSMS, 29.7% of patients in low response (LR) group. The mean vitamin D3 level was (20.42±7.48) ng/mL. The optimal cutoff point for vitamin D3 was 22.25 ng/mL. Univariate logistic regression analysis of SLIT efficacy showed that whether the patient also had a food allergy (P<0.001) or asthma (P=0.011), whether they used acarid products (P=0.002), and whether vitamin D3 is sufficient (P=0.001) were significantly related to the efficacy of SLIT. Multivariate logistic regression analysis showed that after adjusting for whether the patient also had asthma and whether they had used acarid products, whether the patient also had a food allergy (OR: 12.13, 95% CI: 3.57-41.18, P<0.001) and whether vitamin D3 is sufficient (OR: 22.21, 95% CI: 4.04-122.30, P<0.001) were independent factors affecting the efficacy of SLIT. Conclusions: Serum Vitamin D3 deficiency can affect the efficacy of SLIT in children with AR. This study provided a new therapeutic approach for SLIT patients with poor efficacy.

Orientation and cellular distribution of membrane-bound catechol-O-methyltransferase in cortical neurons: implications for drug development.

Catechol-O-methyltransferase (COMT) is a key enzyme for inactivation and metabolism of catechols, including dopamine, norepinephrine, caffeine, and estrogens. It plays an important role in cognition, arousal, pain sensitivity, and stress reactivity in humans and in animal models. The human COMT gene is associated with a diverse spectrum of human behaviors and diseases from cognition and psychiatric disorders to chronic pain and cancer. There are two major forms of COMT proteins, membrane-bound (MB) COMT and soluble (S) COMT. MB-COMT is the main form in the brain. The cellular distribution of MB-COMT in cortical neurons remains unclear and the orientation of MB-COMT on the cellular membrane is controversial. In this study, we demonstrate that MB-COMT is located in the cell body and in axons and dendrites of rat cortical neurons. Analyses of MB-COMT orientation with computer simulation, flow cytometry and a cell surface enzyme assay reveal that the C-terminal catalytic domain of MB-COMT is in the extracellular space, which suggests that MB-COMT can inactivate synaptic and extrasynaptic dopamine on the surface of presynaptic and postsynaptic neurons. Finally, we show that the COMT inhibitor tolcapone induces cell death via the mechanism of apoptosis, and its cytotoxicity is dependent on dosage and correlated with COMT Val/Met genotypes in human lymphoblastoid cells. These results suggest that MB-COMT specific inhibitors can be developed and that tolcapone may be less hazardous at low doses and in specific genetic backgrounds.

Delayed complications of intradural cement leakage after percutaneous vertebroplasty: A case report.

BACKGROUND: Intradural cement leakage following percutaneous vertebroplasty is a rare but acute and devastating complication that usually requires emergent treatment. Here, we report a delayed complication of intradural leakage after percutaneous vertebroplasty. CASE SUMMARY: A 71-year-old female patient with an L1 osteoporotic compression fracture underwent percutaneous vertebroplasty in 2014. She was referred to our hospital 5 years later due to complaints of progressive weakness and numbness in both legs combined with urinary incontinence and constipation. Initially, she was suspected to have a spinal meningioma at the level of L1 according to imaging examinations. Postoperative pathological tests confirmed that cement had leaked into the dura during the first percutaneous vertebroplasty. CONCLUSION: Guideline adherence is essential to prevent cement from leaking into the spinal canal or even the dura. Once leakage occurs, urgent evaluation and decompression surgery are necessary to prevent further neurological damage.

Closed reduction of hip dislocation associated with ipsilateral lower extremity fractures: A case report and review of the literature.

BACKGROUND: Traumatic hip dislocation usually occurs following high-velocity trauma. It is imperative that the dislocation be reduced in a timely manner, especially in a closed manner, as an orthopedic emergency. However, closed reduction can hardly be achieved in patients who also have ipsilateral lower extremity fractures. Herein, we focus on hip dislocation associated with ipsilateral lower extremity fractures, excluding intracapsular fractures (femoral head and neck fractures), present an early closed hip joint reduction method for this injury pattern, and review the literature to discuss the appropriate closed reduction technique for this rare injury pattern. CASE SUMMARY: We report a case of a 37-year-old male who sustained a left acetabular posterior wall fracture, an ipsilateral comminuted subtrochanteric fracture and dislocation of the hip. The hip dislocation was reduced urgently in a closed manner using the joy-stick technique with a T-shaped Schanz screw. The fractures were reduced and fixed as a 2nd-stage surgery procedure. At the 17-month postoperative follow-up, the patient had full range of motion of the affected hip. CONCLUSION: Closed reduction of a hip dislocation associated with ipsilateral lower extremity fractures is rarely achieved by regular maneuvers. Attempts at closed reduction, by means of indirectly controlling the proximal fracture fragment or reconstructing the femoral leverage rapidly with the aid of various external reduction apparatuses, were shown to be effective in some scenarios. Mandatory open reduction is indicated in cases of failed closed reduction, particularly in irreducible dislocations.