Store-operated calcium entry mediates hyperalgesic responses during neuropathy.

Neuropathic pain (NP), resulting from nerve injury, alters neural plasticity in spinal cord and brain via the release of inflammatory mediators. The remodeling of store-operated calcium entry (SOCE) involves the refilling of calcium in the endoplasmic reticulum via STIM1 and Orai1 proteins and is crucial for maintaining neural plasticity and neurotransmitter release. The mechanism underlying SOCE-mediated NP remains largely unknown. In this study, we found SOCE-mediated calcium refilling was significantly higher during neuropathic pain, and the major component Orai1 was specifically co-localized with neuronal markers. Intrathecal injection of SOCE antagonist SKF96365 remarkably alleviated nerve injury- and formalin-induced pain and suppressed c-Fos expression in response to innocuous mechanical stimulation. RNA sequencing revealed that SKF96365 altered the expression of spinal transcription factors, including Fos, Junb, and Socs3, during neuropathic pain. In order to identify the genes critical for SKF96365-induced effects, we performed weighted gene co-expression network analysis (WGCNA) to identify the genes most correlated with paw withdrawal latency phenotypes. Of the 16 modules, MEsalmon module was the most highly correlated with SKF96365 induced effects. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the enriched genes of MEsalmon module were significantly related to Toll-like receptor signaling, steroid biosynthesis, and chemokine signaling, which may mediate the analgesic effect caused by SKF9636 treatment. Additionally, the SOCE antagonist YM-58483 produced similar analgesic effects in nerve injury- and formalin-induced pain. Our results suggest that manipulation of spinal SOCE signaling might be a promising target for pain relief by regulating neurotransmitter production and spinal transcription factor expression.

Polymorphs of a 1:1 salt of sulfadiazine and piperazine-relative stability, dissolution studies, pharmacokinetics and anti-meningitis efficiency.

Two new salt forms of sulfadiazine (SDZ) and piperazine (PIP) were synthesized and characterized. Out of the two polymorphs (SDZ-PIP Ⅰ and SDZ-PIP II), SDZ-PIP Ⅱ is the more stable form at low temperature, room temperature and high temperature. The solution-mediated phase transformation result shows that SDZ-PIP II can transform into pure SDZ within 15 s in phosphate buffer at 37 °C, which leads to a loss in solubility advantage. The addition of 2 mg/mL PVP K30, a polymeric crystallization inhibitor, maintains the solubility advantage and permits supersaturation for a longer period of time. SDZ-PIP II showed 2.5 times the solubility of SDZ alone. The area under the curve (AUC) of SDZ-PIP II with 2 mg/mL PVP K30 was approximately 165% of that of SDZ alone. Moreover, SDZ-PIP II with PVP K30 was more effective than SDZ alone in treating meningitis. Therefore, the SDZ-PIP II salt improves the solubility, bioavailability, and anti-meningitis activity of SDZ.

The Relationship between Personality Traits, Work-Family Support and Job Satisfaction among Frontline Power Grid Workers.

Frontline power grid workers are always facing plenty of stressors such as aerial work and high job demands, which may lead them to be less satisfied with their job. Therefore, this study aims to investigate frontline power grid workers' job satisfaction (JS) and explore how it can be improved by its relationship with personality traits and work-family support (WFS). Data from 535 frontline power grid workers were collected from two power supply bureaus in Guangdong Province, China. Structural equation modeling (SEM) was adopted to examine the structural relationship between personality traits taken as independent variables, JS as dependent variable, and WFS as mediator. The bootstrap method was used to test the significance of indirect effects. Results suggested the overall job satisfaction of our sample is 3.34 ± 0.55 on a scale ranging from 1 to 5, and significantly correlated with personality traits and WFS. Moreover, the results of SEM and bootstrap indicated that WFS partially mediates the effect of neuroticism on JS and fully mediates the effect of conscientiousness and extraversion on JS. These findings shed light on how personality traits and environmental factors jointly impact JS and highlight the important role of WFS among frontline power grid workers.

SKF96365 impedes spinal glutamatergic transmission-mediated neuropathic allodynia.

Spinal nerve injury causes mechanical allodynia and structural imbalance of neurotransmission, which were typically associated with calcium overload. Store-operated calcium entry (SOCE) is considered crucial elements-mediating intracellular calcium homeostasis, ion channel activity, and synaptic plasticity. However, the underlying mechanism of SOCE in mediating neuronal transmitter release and synaptic transmission remains ambiguous in neuropathic pain. Neuropathic rats were operated by spinal nerve ligations. Neurotransmissions were assessed by whole-cell recording in substantia gelatinosa. Immunofluorescence staining of STIM1 with neuronal and glial biomarkers in the spinal dorsal horn. The endoplasmic reticulum stress level was estimated from qRT-PCR. Intrathecal injection of SOCE antagonist SKF96365 dose-dependently alleviated mechanical allodynia in ipsilateral hind paws of neuropathic rats with ED50 of 18 µg. Immunofluorescence staining demonstrated that STIM1 was specifically and significantly expressed in neurons but not astrocytes and microglia in the spinal dorsal horn. Bath application of SKF96365 inhibited enhanced miniature excitatory postsynaptic currents in a dosage-dependent manner without affecting miniature inhibitory postsynaptic currents. Mal-adaption of SOCE was commonly related to endoplasmic reticulum (ER) stress in the central nervous system. SKF96365 markedly suppressed ER stress levels by alleviating mRNA expression of C/EBP homologous protein and heat shock protein 70 in neuropathic rats. Our findings suggested that nerve injury might promote SOCE-mediated calcium levels, resulting in long-term imbalance of spinal synaptic transmission and behavioral sensitization, SKF96365 produces antinociception by alleviating glutamatergic transmission and ER stress. This work demonstrated the involvement of SOCE in neuropathic pain, implying that SOCE might be a potential target for pain management.

Biomaterializing the advances in uterine tissue engineering.

The uterus is considered to be a unique wound-healing model and distinguished by the repeated shedding of the endometrium and self-traceless regeneration. Common curettage, cesarean section, and other operations often cause endometrial and myometrial defects and obstetric and gynecological complications, leading to a high demand for uterine repair or partial replacement. However, the structure and function of the uterus are complicated. Functional uterine tissue engineering requires highly specialized biomaterials with a natural extracellular microenvironment. Currently, no biomaterial can fully simulate the structural and biomechanical properties of the uterus. Many efforts have been made to develop highly functional materials and tissue structures that may provide uterine tissue engineering constructs for reducing obstetric and gynecological complications. Continuous efforts will likely facilitate the development of scalable cells and biomaterial technologies for clinical use. This review summarizes the recent applications of biomaterials and tissue engineering in rebuilding a portion of or the entire uterus.

Visualization for epidemiological modelling: challenges, solutions, reflections and recommendations.

We report on an ongoing collaboration between epidemiological modellers and visualization researchers by documenting and reflecting upon knowledge constructs-a series of ideas, approaches and methods taken from existing visualization research and practice-deployed and developed to support modelling of the COVID-19 pandemic. Structured independent commentary on these efforts is synthesized through iterative reflection to develop: evidence of the effectiveness and value of visualization in this context; open problems upon which the research communities may focus; guidance for future activity of this type and recommendations to safeguard the achievements and promote, advance, secure and prepare for future collaborations of this kind. In describing and comparing a series of related projects that were undertaken in unprecedented conditions, our hope is that this unique report, and its rich interactive supplementary materials, will guide the scientific community in embracing visualization in its observation, analysis and modelling of data as well as in disseminating findings. Equally we hope to encourage the visualization community to engage with impactful science in addressing its emerging data challenges. If we are successful, this showcase of activity may stimulate mutually beneficial engagement between communities with complementary expertise to address problems of significance in epidemiology and beyond. See https://ramp-vis.github.io/RAMPVIS-PhilTransA-Supplement/. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'.

Potential Role of Pain Catastrophic Thinking in Comorbidity Patients of Depression and Chronic Pain.

Background: Although comorbidity of major depressive disorder (MDD) and chronic pain (CP) has been well-studied, their association with pain catastrophizing is largely elusive. This study aimed to investigate the potential effects of pain catastrophizing in patients with a comorbidity. Methods: In total, 140 participants were included in this study and divided into three groups according to the Diagnostic and Statistical Manual of Mental Disorders and the International Association for the study of pain (i.e., the comorbidity group: patients with depression with chronic pain, n = 45; depression group: patients with depression without chronic pain, n = 47; and healthy controls: n = 48). The Hamilton Depression Rating Scale (HAMD)-24 and Hamilton Anxiety Rating Scale (HAMA)-14 were used by professional psychiatrists to evaluate the severity of depression and anxiety. Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI) were conducted by patients' self-report to assess the symptom severity. The pain intensity numerical rating scale (PI-NRS) was used to assess the pain intensity. Pain Catastrophizing Scale (PCS) and Pain Anxiety Symptoms Scale (PASS) were used to estimate pain-related negative thinking. Results: The results showed that PASS and PCS scores were significantly different among the three groups. Particularly, the scores in the comorbidity group were the highest. The Pearson correlation analysis revealed a positive correlation between PCS (including the patients' helplessness, magnification, rumination, and total scores) and the severity of depression symptoms, anxiety symptoms, and pain intensity (P < 0.05). A stepwise regression analysis further demonstrated that the total PCS score, high monthly income level, and BDI score had positive impacts on PASS (P < 0.05). We also found that the total BDI score, disease course ≥1 year, and pain intensity had positive effects on PCS (P < 0.05), whereas years of education (≤ 12 years) had a negative effect on PCS (P = 0.012). In all, we have clearly demonstrated that PCS and PASS could serve as potentially predictive factors in patients suffering from comorbidity of MDD and CP. Conclusion: Our results suggested that the pain-related catastrophic thinking and anxiety were more severe in the comorbidity group than in MDD-only group and healthy group. Pain-related catastrophizing thoughts and anxiety may have potentially effects on the comorbidity of depression and chronic pain.

VIS30K: A Collection of Figures and Tables From IEEE Visualization Conference Publications.

We present the VIS30K dataset, a collection of 29,689 images that represents 30 years of figures and tables from each track of the IEEE Visualization conference series (Vis, SciVis, InfoVis, VAST). VIS30K's comprehensive coverage of the scientific literature in visualization not only reflects the progress of the field but also enables researchers to study the evolution of the state-of-the-art and to find relevant work based on graphical content. We describe the dataset and our semi-automatic collection process, which couples convolutional neural networks (CNN) with curation. Extracting figures and tables semi-automatically allows us to verify that no images are overlooked or extracted erroneously. To improve quality further, we engaged in a peer-search process for high-quality figures from early IEEE Visualization papers. With the resulting data, we also contribute VISImageNavigator (VIN, visimagenavigator.github.io), a web-based tool that facilitates searching and exploring VIS30K by author names, paper keywords, title and abstract, and years.

Explorating the Involvement of Plasma Sestrin2 in Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) can lead to serious complications such as coronary heart disease and hypertension due to oxidative stress. Sestrin2 expression is upregulated under conditions of oxidative stress. This study aimed to explore whether Sestrin2 was involved in OSA. OSA and healthy control subjects were recruited and matched with age, gender, and body mass index (BMI). Plasma Sestrin2 levels were measured and compared. A multivariate stepwise regression model was used to detect the relationship between Sestrin2 and other variable factors. The Sestrin2 levels were compared between before and after four weeks treatment by nasal continuous positive airway pressure (nCPAP) in severe OSA patients. Fifty-seven subjects were divided into two groups: control group (39.33 ± 9.40 years, n = 21) and OSA group (38.81 ± 7.84 years, n = 36). Plasma Sestrin2 levels increased in the OSA group (control group 2.06 ± 1.76 ng/mL, OSA group 4.16 ± 2.37 ng/mL; P = 0.001). Sestrin2 levels decreased after four-week nCPAP treatment (pre-nCPAP 5.21 ± 2.32 ng/mL, post-nCPAP 4.01 ± 1.54 ng/mL; P = 0.004). Sestrin2 was positively correlated with apnea/hypopnea index (AHI) oxygen desaturation index, while negatively correlated with mean oxygen saturation. Moreover, these correlations remained unchanged after adjusting for gender, age, waist-to-hip ratio, and body mass index. Multiple regression analysis showed that there was an association between Sestrin2 and AHI. Our findings suggest that Sestrin2 is involved in OSA. The increase of plasma Sestrin2 is directly related to the severity of OSA. To some extent, Sestrin2 may be useful for determining the severity of OSA and monitoring the effect of CPAP. In addition, since some complications of OSA such as coronary heart disease and diabetes are usually related with oxidative stress, the role of Sestrin2 in those OSA complications needs further study.

Physical Activity and Risk of Breast Cancer: A Meta-Analysis of 38 Cohort Studies in 45 Study Reports.

OBJECTIVES: To evaluate and quantify the association between physical activity (PA) and risk of breast cancer. METHODS: A systematic review meta-analysis was conducted. The literature was independently and manually searched by 2 reviewers through 3 English databases (PubMed, Embase, and ISI Web of Science) for data till October 2017. The quality of included studies was assessed by the Newcastle-Ottawa Quality Assessment Scale. Fixed-effects models were used to estimate the pooled relative risk and 95% confidence intervals (95% CI). Dose-response analysis was chosen for quantifying the association between PA and risk of breast cancer. The Begg test and the Egger test were used to estimate potential publication bias. Heterogeneity between studies was evaluated with I2 statistics. RESULTS: The meta-analysis included 38 cohort studies published between 1994 and 2017, which included 68 416 breast cancer cases. The overall relative risk (ORR) for breast cancer was 0.87 (95% CI 0.84-0.90). The inverse association was consistent among all subgroup analyses. In subgroup analysis by menopausal status, the ORR of breast cancer was 0.83 (95% CI 0.79-0.87) for premenopausal status and 0.91 (95% CI 0.85-0.97) for postmenopausal status. In subgroup analysis by PA type, the ORR for total activity was 0.87 (95% CI 0.81-0.93), for recreational activity 0.88 (95% CI 0.85-0.91), for occupational activity 0.91 (95% CI 0.84-0.99), and for nonoccupational activity 0.87 (95% CI 0.83-0.92). The risk of breast cancer was significantly lower in people with exposure periods longer than 1 year and less than 5 years (ORR 0.62; 95% CI 0.46-0.78), followed by those with lifetime activity (ORR 0.81; 95% CI 0.69-0.93). The ORR for subjects with body mass index of less than 25 kg/m2 (0.88; 95% CI 0.83-0.93) was close to that for subjects with body mass index of more than 25 kg/m2 (0.87; 95% CI 0.77-0.97). A linear relationship was found between breast cancer risk and PA (recreational activity and total activity), and the ORR was reduced by 3% (95% CI 0.95-0.99) for every 10 metabolic equivalent of energy hours per week increment in recreational PA and by 2% (95% CI 0.97-0.99) for every 10 metabolic equivalent of energy hours per week increment in total PA. CONCLUSIONS: PA is significantly associated with a decrease in the risk of breast cancer.

Effect of sociodemographic and physical activity on cognitive function in older adults: A nationwide cross-sectional survey.

OBJECTIVE: We aimed to assess the effect of socioeconomic status and physical activity on cognitive function using a large population-based survey data in China. METHODS: We took advantage of the Chinese Longitudinal Healthy Longevity Survey conducted in 2014 to examine the relationship between sociodemographic, physical activity, and cognitive function in older adults (OAs) for persons aged above 65 (N = 2848). Socioeconomic status was assessed by sex, age, co-residence situation, category of residence, years of schooling, and marital status. Multiple linear regression for predictors was utilized. Physical activity was assessed using activities of daily living (ADL) and instrumental activities of daily living (IADL) measures. Cognitive function was assessed by the Modified Mini-Mental State Examination. RESULTS: The mean age of the OAs was 80.65 years (SD = 8.55). Their mean Mini-Mental State Examination score was 21.55 (SD = 2.38), mean ADL Total score was 6.24 (SD = 0.95), and mean IADL Total score was 10.21 (SD = 3.84). OAs' age at testing, co-residence and category of residence significantly predicted both ADL Total score and IADL Total score (P < 0.05), sex significantly predicted IADL Total score (R2  = 0.02, ß = 0.13, P = 0.000) but not ADL Total score (R2  = 0.00, ß = 0.02, P = 0.211). OAs' sex, age, co-residence, and years of schooling significantly predicted cognitive function (P < 0.05), IADL total score significantly predicted cognitive function (P < 0.01), while the relationship between ADL total score and cognitive function was not significant (P = 0.94). CONCLUSION: OAs' sex, age, co-residence, years of schooling, and IADL were significantly associated with cognitive function. Improving OAs' IADL, especially in lower social classes, may help to improve the overall cognitive function of the OAs.

Upregulation of ADAM12 contributes to accelerated cell proliferation and cell adhesion-mediated drug resistance (CAM-DR) in Non-Hodgkin's Lymphoma.

OBJECTIVE: ADAM12 is a member of a disintegrin and metalloproteinase family and has been reported to participate in the development of variety of tumors. However, the role of ADAM12 in Non-Hodgkin Lymphoma (NHL) has not been investigated. The present study was undertaken to determine the expression and biologic function of ADAM12 in human NHL. METHODS: First, we constructed a model of cell adhesion in NHL, the mRNA, and protein level of ADAM12 in suspension and the adhesion model was analyzed by RT-PCR and western blot. Then, flow cytometry assay and western blot were used to investigate the mechanism of ADAM12 in the proliferation of NHL cells. In vitro, after using siRNA interfering ADAM12 expression, we performed adhesion assay and cell viability assay to determine the effect of ADAM12 on adhesive rate and drug sensitivity. RESULTS: ADAM12 was lowly expressed in suspended cells and highly expressed in adherent NHL cells. In addition, ADAM12 was positively correlated with the proliferation and apoptosis of NHL cells by regulating the expression of p-AKT and p-GSK-3ß. Furthermore, ADAM12 promoted cell adhesion-mediated drug resistance (CAM-DR) in DLBCL via AKT signaling pathway. CONCLUSION AND DISCUSSION: Our data support a role for ADAM12 in NHL cell proliferation, adhesion, and drug resistance, and it may pave the way for a novel therapeutic approach for CAM-DR in NHL.

ADP-ribosylation factor 1 (ARF1) takes part in cell proliferation and cell adhesion-mediated drug resistance (CAM-DR).

Cell adhesion-mediated drug resistance (CAM-DR) remains the primary obstacle in human multiple myeloma (MM) therapy. In this study, we aimed at investigating the expression and biologic function of ARF1 in MM. We determined that ARF1 expression was positively correlated with cell proliferation and knockdown of ARF1 contributed to CAM-DR. The enhancement in the adhesion of MM cells to fibronectin (FN) or the bone marrow stroma cell line HS-5 cells translated to an increased CAM-DR phenotype. Importantly, we showed that this CAM-DR phenotype was correlated with the phosphorylation of Akt and ERK in MM cells. Moreover, we sought to determine whether ARF1 could interact with p27 in RPMI8226 cells. Knockdown of ARF1 also significantly decreased pT157-p27 protein expression in RPMI8226 cells. Our research shows ARF1 may reverse CAM-DR by regulating phosphorylation of p27 at T157 in MM. Taken together, our data shed new light on the molecular mechanism of CAM-DR in MM, and targeting ARF1 may be a novel therapeutic approach for improving the effectiveness of chemotherapy in MM.

A New Cytotoxic Cyclolanostane Triterpenoid Xyloside from Souliea vaginata.

A new cyclolanostane triterpenoid xyloside, soulieoside P (1), and a known oleanane-type saponin, hederasaponin B (2), were isolated from the rhizomes of Souliea vaginata. Their structures were established by extensive spectroscopic and HRESIMS analysis, as well as chemical methods. Compound 1 showed significant inhibitory effects with IC50 values of 7.6-11.2 µM against three human cancer cell lines, while compound 2 exhibited no hepatoprotective effect on CCI4-induced injury of human HepG2 cells, in the tested range of 0.1-100 µM.

Silencing of CKIP-1 promotes tumor proliferation and cell adhesion-mediated drug resistance via regulating AKT activity in non-Hodgkin's lymphoma.

Casein kinase 2 interacting protein-1 (CKIP-1; also known as PLEKHO1) is involved in regulating many processes such as cell proliferation, differentiation and apoptosis. CKIP-1 also plays an important role in many types of cancer, such as colon, breast cancer and human osteosarcoma. In the present study, we found that CKIP-1 was reversely associated with the proliferation of non-Hodgkin's lymphoma (NHL) and cell adhesion mediated drug resistance (CAM-DR). We demonstrated that knockdown of CKIP-1 promoted the proliferation of NHL cells through interacting with Akt and suppressing Akt phosphorylation. In addition, adhesion of lymphoma cells to fibronectin or stroma cells (HS-5 cells) decreased CKIP-1 expression, which led to the upregulation of Akt phosphorylation. Importantly, we showed that the phosphorylation of Akt was correlated with CAM-DR phenotype in NHL cells. Taken together, the present study shed new light on the molecular mechanism of CAM-DR in NHL and targeting CKIP-1 may be a novel therapeutic target for NHL.

DIXDC1 promotes tumor proliferation and cell adhesion mediated drug resistance (CAM-DR) via enhancing p-Akt in Non-Hodgkin's lymphomas.

DIX domain containing 1 (DIXDC1), is a human homolog of Ccd1, a DIX domain containing protein in zebrafish. The present study was undertaken to determine the expression and biologic function of DIXDC1 in Non-Hodgkin's lymphoma (NHL). Clinically, we detected that the expression of DIXDC1 was significantly lower in the indolent lymphomas compared with the progressive lymphomas by immunohistochemistry analysis. Functionally, we found that DIXDC1 could promote cell proliferation via modulating cell cycle progression and PI3K/AKT signaling pathway in NHLs. Moreover, we confirmed that DIXDC1 was involved in the process of lymphoma cell adhesion mediated drug resistance (CAM-DR). Adhesion to fibronectin (FN) or HS-5 up-regulated DIXDC1 expression, and up-regulation of DIXDC1 resulted in an increased expression of p-AKT, which promoted CAM-DR. Our finding supports the role of DIXDC1 in cell proliferation, cell cycle and CAM-DR in NHLs. We propose that inhibition of DIXDC1 expression may be a novel therapeutic approach for NHLs patients, and it may be a target for drug resistance.

Expression of vaccinia-related kinase 1 (VRK1) accelerates cell proliferation but overcomes cell adhesion mediated drug resistance (CAM-DR) in multiple myeloma.

OBJECTIVE: Vaccinia-related kinase 1 (VRK1) has been reported to participate in the development of a variety of tumors. However, the role of VRK1 in multiple myeloma (MM) has not been investigated. The present study was undertaken to determine the expression and biologic function of VRK1 in human MM. METHODS: First, we constructed a model of cell adhesion in MM, the mRNA and protein level of VRK1 in suspension and adhesion model was analyzed by RT-PCR and western blot. Then, flow cytometry assay and western blot were used to investigate the mechanism of VRK1 in the proliferation of MM cells. In vitro, following using shRNA interfering VRK1 expression, we performed adhesion assay and cell viability assay to determine the effect of VRK1 on adhesive rate and drug sensitivity. RESULTS: VRK1 was lowly expressed in adherent MM cells and highly expressed in suspended cells. In addition, VRK1 was positively correlated with the proliferation of MM cells by regulating the expression of cell cycle-related protein, such as cyclinD1, CDK2 and p27kip1. Furthermore, VRK1 could reverse cell adhesion mediated drug resistance (CAM-DR) by down-regulating the ability of cell adhesion. CONCLUSION AND DISCUSSION: Our data supports a role for VRK1 in MM cell proliferation, adhesion, and drug resistance, and it may pave the way for a novel therapeutic approach for CAM-DR in MM.