A Study on Prognosis of Diffuse Glioma Based on Clinical Factors and Magnetic Resonance Imaging Radiomics.

OBJECTIVE: To construct an optimal prognostic model to assess the prognosis of patients with diffuse glioma. METHODS: Preoperative magnetic resonance imaging and clinical data were retrospectively collected from 266 patients (training cohort: validation cohort=7:3) with pathologically confirmed diffuse gliomas. A radiomics prognostic model (R-model) based on the radiomics features was constructed. A prognostic model based on clinical factors (C-model) and a fusion model (F-model) was also constructed. Based on the optimal model of three models, the nomogram was constructed. Finally, a "Prognosis Calculator for Diffuse Glioma" was constructed based on the nomogram. RESULTS: The c-index of the R-, C-, and F-models in the validation cohort was 0.742, 0.796, and 0.814, respectively. In the validation cohort, the 1-year area under the curve of the R-, C-, and F-models was 0.749, 0.806, and 0.836, respectively; the 3-year area under the curve was 0.896, 0.966, and 0.963, respectively. In the training cohort, validation cohort, all cohorts, and different grades of glioma cohorts, F-model (optimal model) could identify low- and high-risk groups well. The "Prognosis Calculator for Diffuse Glioma" was available at https://github.com/HDCurry/prognosis. CONCLUSIONS: Among the three models, the F-model (radiomics combined with clinical factors) had optimal predictive efficacy and could more accurately assess the prognosis of diffuse glioma. The "Prognosis Calculator for Diffuse Glioma" constructed based on this model could assist clinicians in more easily and accurately assessing the prognosis of patients with diffuse glioma, thus enabling them to make more reasonable treatment strategies.

Quadratus lumborum block vs. transversus abdominis plane block for postoperative pain control in patients with nephrectomy: A systematic review and network meta-analysis.

STUDY OBJECTIVE: This systematic review and network meta-analysis aimed to compare the analgesic efficacy of transversus abdominis plane block (TAPB) and quadratus lumborum block (QLB) on nephrectomy. DESIGN: Systematic review and network meta-analysis. PATIENTS: Patients undergoing nephrectomy. INTERVENTIONS: TAPB and QLB for postoperative analgesia. MEASUREMENTS: The primary outcome was 24 h morphine-equivalent consumptions after surgery. Secondary outcomes included postoperative pain scores, postoperative opioid consumption, postoperative rescue analgesia, postoperative nausea and vomiting (PONV), length of hospital stay after surgery, and patient satisfaction. MAIN RESULTS: Fourteen studies involving 883 patients were included. Seven studies compared TAPB to control, six studies compared QLB to control, and one study compared TAPB to QLB. For direct meta-analysis of the post-surgical 24 h morphine-equivalent consumption, QLB was lower than control (mean difference [95%CI]: -18.16 [-28.96, -7.37]; I2 = 88%; p = 0.001), while there was no difference between TAPB and control (mean difference [95%CI]: -8.34 [-17.84, 1.17]; I2 = 88%; p = 0.09). Network meta-analysis showed similar findings that QLB was ranked as the best anesthetic technique for reducing postoperative 24 h opioid consumption (p-score = 0.854). Moreover, in direct meta-analysis, as compared to control, the time of first postoperative rescue analgesia was prolonged after QLB (mean difference [95%CI]: 165.00 [128.99, 201.01]; p < 0.00001), but not TAPB (mean difference [95%CI]: 296.82 [-91.92, 685.55]; p = 0.13). Meanwhile, QLB can effectively reduce opioid usages at intraoperative period, as well as at postoperative 6 h and 48 h, while TAPB can only reduce opioid consumption at 6 h after surgery. As compared to control, both TAPB and QLB exhibited the reduction in PONV and pain scores at post-surgical some timepoints. Also, QLB (mean difference [95%CI]: -0.29 [-0.49, -0.08]; p = 0.006) but not TAPB (mean difference [95%CI]: 0.60 [-0.25, 1.45]; p = 0.17) exhibited the shorter postoperative length of hospital stay than control. CONCLUSIONS: QLB is more likely to be effective in reducing postoperative opioid use than TAPB, whereas both of them are superior to control with regard to the reduction in postoperative pain intensity and PONV. TRIAL REGISTRATION: PROSPERO identifier: CRD42022358464.

Structural basis of peptide recognition and activation of endothelin receptors.

Endothelin system comprises three endogenous 21-amino-acid peptide ligands endothelin-1, -2, and -3 (ET-1/2/3), and two G protein-coupled receptor (GPCR) subtypes-endothelin receptor A (ETAR) and B (ETBR). Since ET-1, the first endothelin, was identified in 1988 as one of the most potent endothelial cell-derived vasoconstrictor peptides with long-lasting actions, the endothelin system has attracted extensive attention due to its critical role in vasoregulation and close relevance in cardiovascular-related diseases. Here we present three cryo-electron microscopy structures of ETAR and ETBR bound to ET-1 and ETBR bound to the selective peptide IRL1620. These structures reveal a highly conserved recognition mode of ET-1 and characterize the ligand selectivity by ETRs. They also present several conformation features of the active ETRs, thus revealing a specific activation mechanism. Together, these findings deepen our understanding of endothelin system regulation and offer an opportunity to design selective drugs targeting specific ETR subtypes.

A randomized controlled trial evaluating the effects of transversus abdominis plane block with compound lidocaine hydrochloride injection on postoperative pain and opioid consumption and gastrointestinal motility in patients undergoing gynecological laparotomy.

Introduction: Incorporation of transversus abdominis plane (TAP) block into multimodal analgesia has been emphasized in Enhanced Recovery protocols (ERPs). However, benefit is limited in clinical practice. A potential explanation is the short duration of analgesia of standard local anesthetics. Herein, this randomized, double-blind, controlled trial evaluated whether TAPB with long-acting compound lidocaine hydrochloride injection reduces postoperative pain. Methods: 164 patients undergoing elective gynecological laparotomy under sevoflurane anesthesia randomly received ultrasound-guided TAP block with either saline, or ropivacaine, or compound lidocaine before anesthesia induction. The postoperative pain intensity (primary outcome) was evaluated by pain 11-point numerical rating scale. We also recorded sufentanil consumptions, time to first flatus, side-effects and hospital stay after surgery. Results: We reported that pain scores at rest at postoperative 3h in group 0.375% ropivacaine was lower than that in group saline [mean 2.4 (SD 1.2) vs. 3.0 (1.0), p = 0.036]. Compared with saline, 0.4% and 0.6% compound lidocaine caused lower pain scores at rest at postoperative 12h [2.8 (0.9) vs. 2.1 (0.9) and 2.0 (0.9), p = 0.016 and p = 0.006]. Sufentanil usage for the first postoperative 48h was lower in group 0.6% compound lidocaine than group saline [24.2 (5.4) vs. 45.6 (7.5) µg, p < 0.001]. Time to first flatus and hospital stay after surgery was shortest and the incidence of postoperative nausea was lowest in patients receiving 0.6% compound lidocaine. Conclusion: TAP block with 0.6% compound lidocaine hydrochloride injection attenuates postoperative pain, reduces opioid consumption, accelerates gastrointestinal function recovery, and shortens length of hospital stay in patients after gynecological laparotomy. Trial registration: ClinicalTrials.gov, identifier: NCT04938882.

Nalmefene vs. dexmedetomidine for prevention of postoperative hyperalgesia in patients undergoing laparoscopic gynecological surgery with remifentanil infusion: A randomized double-blind controlled trial.

Intraoperative remifentanil infusion may paradoxically induce post-surgical hyperalgesia. Dexmedetomidine reportedly reduces opioid-induced hyperalgesia. Nalmefene selectively reverses several side-effects of opioids without impairing analgesia. Herein, this randomized, double-blind controlled trial investigated whether nalmefene, dexmedetomidine, and both drugs combined prevent remifentanil-induced hyperalgesia. One hundred and fifty patients undergoing elective laparoscopic gynecological surgery under desflurane anesthesia randomly received either intraoperative sufentanil 0.20 µg kg-1 (Group S), or remifentanil 0.20 µg kg-1 min-1 (Group R), or remifentanil and pre-anesthesia nalmefene 0.20 µg kg-1 (Group N), or remifentanil and pre-anesthesia dexmedetomidine 0.50 µg kg-1 (Group D), or remifentanil and the combination of dexmedetomidine 0.25 µg kg-1 and nalmefene 0.10 µg kg-1 (Group DN). The threshold of postoperative mechanical hyperalgesia (primary outcome) was measured with von Frey filaments. We also recorded pain intensity, analgesic consumptions, hyperalgesic area, and side-effects for 24 h postoperatively. Compared with Group S, remifentanil reduced hyperalgesic threshold on the forearm [mean 89.4 (SD 13.7) vs. 62.2 (10.7) g, p < 0.001] at postoperative 24 h. Pain threshold on the forearm at postoperative 24 h was significantly lower in Group R than in Groups N, D and DN [62.2 (10.7) vs. 71.1 (12.3), 72.4 (12.9) and 78.0 (13.8) g]. Compared with Group R, Postoperative pain intensity, analgesic consumption and hyperalgesic area were lower likewise in Groups D and DN. However, the incidence of intraoperative bradycardia was lower and post-anesthesia recovery time was shorter in Group DN than Group D. Preoperative therapy of dexmedetomidine and nalmefene combined attenuates postoperative hyperalgesia in patients undergoing laparoscopic gynecological surgery under desflurane-remifentanil anesthesia.

Biomimetic nanoprodrugs from fatty acid modified camptothecin and albumin for enhanced pharmacotherapy.

Design of nanovectors inspired by nature is a short cut to improve the efficacy and bioavailability of chemotherapeutic agents, while reduce the toxicity. In this work, strongly hydrophobic camptothecin (CPT) was modified with different chain length of fatty acid (C4, C9 and C18) to synthesize CPT4C, CPT9C and CPT18C, respectively. CPT4C, CPT9C and CPT18C could complex with human serum albumin (HSA) readily to prepare CPT4C-HSA, CPT9C-HSA and CPT18C-HSA nanoagents. In vitro MTT assays demonstrated CPT18C-HSA possessed the highest cell killing capacity, due to the elevated cellular uptake that resulted from albumin-mediated transportation. In vivo tumor inhibition experiments verified that CPT18C-HSA had the most remarkable antitumor efficiency with distinctly lowered physiological toxicity. It could be used in large doses without obvious side effects. We believe this albumin-mediated transportation mode has great potential for efficient delivery of hydrophobic and/or physiologically unstable drugs.

SKF83959 Attenuates Memory Impairment and Depressive-like Behavior during the Latent Period of Epilepsy via Allosteric Activation of the Sigma-1 Receptor.

Memory impairment and emotional disorder are two common clinical comorbidities in patients with epilepsy. It is imperative to develop a novel therapeutic agent or a strategy. 6-Chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) is a dopamine-1 receptor agonist and sigma-1 receptor allosteric modulator, which displays the neuron-protective and anti-neuroinflammation activity. We examined the effect of SKF83959 on the memory impairment and emotional disorder in the latent period of epilepsy using the mice post-status epilepticus model. We found that SKF83959 ameliorated memory impairment and depressive-like mood, alleviated the neuron damage and the formation of gliosis in hippocampus, suppressed the rise of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß, and induced nitric oxide synthase in the latent period of epilepsy. Additionally, SKF83959 significantly inhibited the activity of calcineurin and glycogen synthase kinase-3ß. All of these protective actions were reversed by BD1047 (a sigma-1 receptor antagonist). In addition, the intra-hippocampus injection of ketoconazole (a dehydroepiandrosterone synthesis inhibitor) also reversed the protective activity of SKF83959. Thus, we concluded that SKF83959 ameliorated the memory impairment and depressive-like mood in epilepsy via allosterically activating the sigma-1 receptor and subsequently inhibiting the calcineurin/glycogen synthase kinase-3ß pathway.

Predictive value of baseline metabolic tumor volume for non-small-cell lung cancer patients treated with immune checkpoint inhibitors: A meta-analysis.

Background: Immune checkpoint inhibitors (ICIs) have emerged as a promising treatment option for advanced non-small-cell lung cancer (NSCLC) patients, highlighting the need for biomarkers to identify responders and predict the outcome of ICIs. The purpose of this study was to evaluate the predictive value of baseline standardized uptake value (SUV), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) derived from 18F-FDG-PET/CT in advanced NSCLC patients receiving ICIs. Methods: PubMed and Web of Science databases were searched from January 1st, 2011 to July 18th, 2022, utilizing the search terms "non-small-cell lung cancer", "PET/CT", "standardized uptake value", "metabolic tumor volume", " total lesion glycolysis", and "immune checkpoint inhibitors". Studies that analyzed the association between PET/CT parameters and objective response, immune-related adverse events (irAEs) and prognosis of NSCLC patients treated with ICIs were included. We extracted the hazard ratio (HR) with a 95% confidence interval (CI) for progression-free survival (PFS) and overall survival (OS). We performed a meta-analysis of HR using Review Manager v.5.4.1. Results: Sixteen studies were included for review and thirteen for meta-analysis covering 770 patients. As for objective response and irAEs after ICIs, more studies with consistent assessment methods are needed to determine their relationship with MTV. In the meta-analysis, low SUVmax corresponded to poor PFS with a pooled HR of 0.74 (95% CI, 0.57-0.96, P=0.02). And a high level of baseline MTV level was related to shorter PFS (HR=1.45, 95% CI, 1.11-1.89, P<0.01) and OS (HR, 2.72; 95% CI, 1.97-3.73, P<0.01) especially when the cut-off value was set between 50-100 cm3. SUVmean and TLG were not associated with the prognosis of NSCLC patients receiving ICIs. Conclusions: High level of baseline MTV corresponded to shorter PFS and OS, especially when the cut-off value was set between 50-100 cm3. MTV is a potential predictive value for the outcome of ICIs in NSCLC patients.

Self-Adaptive Flask-like Nanomotors Based on Fe3O4 Nanoparticles to a Physiological pH.

In living bodies, pH values, which are precisely regulated and closely associated with diseased cells, can act as an efficient biologically intrinsic indicator for future intelligent biomedicine microsystems. In this work, we have developed flask-like carbonaceous nanomotors (FCNMs), via loading Fe3O4 nanoparticles (NPs) into a cavity, which exhibit a self-adaptive feature to a specific physiological pH by virtue of the pH-dependent dual enzyme-like activities of Fe3O4 NPs. Specifically, the peroxidase-like activity of Fe3O4 NPs in an acidic pH range, and the catalase-like activity in a near neutral and alkaline pH range, determine the products in the motion system (•OH, ions and O2), whose diffusions from the inner to the outside of the flask result in fluid movement providing the driving force for the movement of the FCNMs. Correspondingly, changes of the product concentrations and species in the physiological pH range (4.4-7.4) result, firstly, in velocity decrease and, then, with increase in pH, increase of the FCNMs occurs. Thanks to the non-linear velocity responsiveness, the FCNMs show intriguing pH taxis towards 6.8 (generally corresponding to the physiological pH in tumor microenvironments), where a maximum velocity appears. Furthermore, the superparamagnetic feature of the Fe3O4 NPs simultaneously endows the FCNMs with the abilities to be magnetic-oriented and easily separated. This work could significantly increase the possibility of nanomotors for targeted therapy of tumors and next-generation biotechnological applications.

Artesunate Therapy Alleviates Fracture-Associated Chronic Pain After Orthopedic Surgery by Suppressing CCL21-Dependent TREM2/DAP12 Inflammatory Signaling in Mice.

Chronic pain after bone fracture and orthopedic surgery is often refractory to most analgesics currently in use, thus emphasizing the urgent need for improved therapeutic medications. Chemokine-dependent neuroinflammation is critical for excitatory synaptic plasticity and central nociception sensitization. Recent studies have focused on the inhibition of inflammatory responses by artesunate, the first anti-malaria drug extracted from artemisinin. The present study investigated the analgesic effects and potential targets of artesunate in a mouse model of chronic pain induced by tibial fracture and orthopedic surgery. Three injections of artesunate were intrathecally administered on a daily basis from days 4 to 6 after fracture. We reported that repetitive exposure to artesunate (10 and 100 µg but not 1 µg) dose-dependently prevented fracture-induced mechanical and cold allodynia. Moreover, single intrathecal injection of artesunate (100 µg) alleviated the established chronic pain on day 14 after fracture surgery. Intraperitoneal artesunate (10 and 50 mg kg-1) therapy was effective against chronic fracture pain. Intriguingly, artesunate inhibited the upregulation of spinal chemokine CCL21, triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12) expressions and microglia activation in fracture mice. Furthermore, spinal CCL21 neutralization attenuated the severity of fracture-associated post-surgical pain. Exogenous CCL21-induced acute inflammatory pain was impaired by artesunate therapy. Additionally, the pharmacological blockage of TREM2 reduced recombinant CCL21-elicited behavioral hypernociception. The present findings demonstrate that artesunate therapy reduces the initiation and maintenance of fracture-associated chronic postoperative pain by inhibiting CCL21-dependent TREM2/DAP12 inflammatory signaling and microglia activation, thus suggesting that artesunate could emerge as a therapeutic strategy for fracture pain management.

Toxoplasma gondii infection as a risk factor for osteoporosis: a case-control study.

BACKGROUND: More than one-third of the total world population is infected by Toxoplasma gondii (T. gondii). T. gondii has been linked to various diseases, such as cancer, mental disorders, type 2 diabetes mellitus (T2DM), etc. However, the effects of T. gondii infection on the risk of osteoporosis are unclear. Our study aimed to uncover evidence to determine whether patients exposed to T. gondii have an increased or decreased risk of osteoporosis in people with abnormal bone mineral density (BMD) by using case-control study. METHODS: A total of 729 patients, including 316 osteopenia and 413 osteoporosis patients of Han Chinese ancestry were selected in the study. Their blood samples were collected and the levels of specific IgG antibodies against T. gondii were measured using ELISA assay. We obtained some information about the patients from the medical record that included demographic indexes and clinical data. A logistic regression analysis was used to evaluate the effects of T. gondii infection on femur osteoporosis, lumbar osteoporosis and compound osteoporosis. Potential interaction was analyzed using multifactor dimensionality reduction software 1.0.0 (MDR 1.0.0). RESULTS: 113 positive patients with T. gondii infections have been detected, including 80 cases of osteoporosis and 33 cases of osteopenia, the infection rates of T. gondii were 19.37% (80/413) and 10.44% (33/316), respectively. The patients with T.gondii infections were at a 2.60 times higher risk of suffering from compound osteoporosis than those without T. gondii infections (OR = 2.60, 95% CI 1.54-4.39, P < 0.001), but not associated with femur osteoporosis (OR = 1.01, 95% CI 0.43-2.34, P = 0.989) and lumbar osteoporosis (OR = 0.84, 95% CI 0.34-2.07, P = 0.705) after adjusting for the covariates. Moreover, a significantly higher risk of compound osteoporosis in the individuals with all two factors (T. gondii infection, Female) was observed compared with reference group (without T. gondii infection, male) under the interaction model (OR = 11.44, 95%CI = 5.44-24.05, P < 0.001). And the individuals with all two factors (T. gondii infection, over 70 years) exhibited a 8.14-fold higher possibility of developing compound osteoporosis compared with reference group (without T. gondii infection, under 70 years) (OR = 8.14, 95% CI 3.91-16.93, P < 0.001). We further stratified by age and sex, and found that women with T. gondii infection was more likely to develop compound osteoporosis than those without infection(OR = 3.12, 95% CI 1.67-5.81, P < 0.001), but we not found the association between T. gondii infection and compound osteoporosis in males (OR = 1.36, 95% CI 0.37-4.94, P = 0.645). CONCLUSIONS: T. gondii infection is a risk factor for osteoporosis, especially compound osteoporosis. Meanwhile, it is very necessary for patients with osteoporosis to further diagnose and treat T. gondii infection, especially women.

Inhibition of Noncanonical Ca2+ Oscillation/Calcineurin/GSK-3ß Pathway Contributes to Anti-Inflammatory Effect of Sigma-1 Receptor Activation.

Further understanding the mechanism for microglia activation is necessary for developing novel anti-inflammatory strategies. Our previous study found that the activation of sigma-1 receptor can effectively inhibit the neuroinflammation, independent of the canonical mechanisms, such as NF-κB, JNK and ERK inflammatory pathways. Thus, it is reasonable that an un-identified, non-canonical pathway contributes to the activation of microglia. In the present study, we found that a sigma-1 receptor agonist of 2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate (PRE-084) suppressed lipopolysaccharide (LPS) elevated nitric oxide (NO) content in BV-2 microglia culture supernatant and LPS-raised mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), inducible nitric oxide synthase (iNOS) in BV-2 microglia. Moreover, PRE-084 alleviated LPS-increased Ser 9 de-phosphorylation of glycogen synthase kinase-3 beta (GSK-3ß), LPS-elevated catalytic activity of calcineurin, and LPS-raised percent and frequency of Ca2+ oscillatory BV-2 cells. We further found that the inhibitory effect of PRE-084 was reversed by a calcineurin activator of chlorogenic acid and a GSK-3ß activator of pyrvinium. Moreover, an IP3 receptor inhibitor of 2-aminoethoxydiphenyl borate mimicked the anti-inflammatory activity of PRE-084. Thus, we identified a noncanonical pro-neuroinflammary pathway of Ca2+ oscillation/Calcineurin/GSK-3ß and the inhibition of this pathway is necessary for the anti-inflammatory activity of sigma-1 receptor activation.

Development of an interpretable machine learning-based intelligent system of exercise prescription for cardio-oncology preventive care: A study protocol.

Background: Cardiovascular disease (CVD) and cancer are the first and second causes of death in over 130 countries across the world. They are also among the top three causes in almost 180 countries worldwide. Cardiovascular complications are often noticed in cancer patients, with nearly 20% exhibiting cardiovascular comorbidities. Physical exercise may be helpful for cancer survivors and people living with cancer (PLWC), as it prevents relapses, CVD, and cardiotoxicity. Therefore, it is beneficial to recommend exercise as part of cardio-oncology preventive care. Objective: With the progress of deep learning algorithms and the improvement of big data processing techniques, artificial intelligence (AI) has gradually become popular in the fields of medicine and healthcare. In the context of the shortage of medical resources in China, it is of great significance to adopt AI and machine learning methods for prescription recommendations. This study aims to develop an interpretable machine learning-based intelligent system of exercise prescription for cardio-oncology preventive care, and this paper presents the study protocol. Methods: This will be a retrospective machine learning modeling cohort study with interventional methods (i.e., exercise prescription). We will recruit PLWC participants at baseline (from 1 January 2025 to 31 December 2026) and follow up over several years (from 1 January 2027 to 31 December 2028). Specifically, participants will be eligible if they are (1) PLWC in Stage I or cancer survivors from Stage I; (2) aged between 18 and 55 years; (3) interested in physical exercise for rehabilitation; (4) willing to wear smart sensors/watches; (5) assessed by doctors as suitable for exercise interventions. At baseline, clinical exercise physiologist certificated by the joint training program (from 1 January 2023 to 31 December 2024) of American College of Sports Medicine and Chinese Association of Sports Medicine will recommend exercise prescription to each participant. During the follow-up, effective exercise prescription will be determined by assessing the CVD status of the participants. Expected outcomes: This study aims to develop not only an interpretable machine learning model to recommend exercise prescription but also an intelligent system of exercise prescription for precision cardio-oncology preventive care. Ethics: This study is approved by Human Experimental Ethics Inspection of Guangzhou Sport University. Clinical trial registration: http://www.chictr.org.cn, identifier ChiCTR2300077887.

Stimulation of astrocytic sigma-1 receptor is sufficient to ameliorate inflammation- induced depression.

Astrocytes play important roles in the development of depression. As a promising target for antidepressant development, sigma-1 receptor (Sig-1R) is reported to promote activation of astrocyte in chronic stress-induced depression in our previous study. However, astrocytes are hyper-activated in inflammation-induced depression, raising concerns of whether stimulation of astrocytic Sig-1R would exert antidepressant-like effect in inflammation-induced depression. Here we reported that specific stimulation of astrocytic Sig-1R using adeno-associated virus (AAV) significantly attenuated lipopolysaccharide (LPS)- induced depressive-like behavior in the forced swim test (FST), tail suspension test (TST), sucrose preference test, and improved the memory function in novel object recognition test. Besides, specific stimulation of astrocytic Sig-1R decreased the activation of astrocyte and microglia, as well as increased brain-derived neurotrophic factor (BDNF) in LPS-induced depression. In primary cultured astrocytes, overexpression of Sig-1R also reduced the expression of IL-1ß, TNF-α, iNOS during inflammation-treated astrocyte. Taken together, the results suggest that specific stimulation of astrocytic Sig-1R ameliorates inflammation-induced depressive-like behavior, providing the evidence that astrocytic Sig-1R could represent a reliable therapeutic target for depression.

Microscale strain mapping demonstrates the importance of interface slope in the mechanics of cartilage repair.

Achieving lateral integration of articular cartilage repair tissue with surrounding native cartilage remains a clinical challenge. Histological and bulk mechanical studies have identified extracellular matrix components that correlate with superior failure strength, but it is unclear how local changes in geometry and composition at the repair interface affect tissue strains under physiologic loading. Here, we investigated the effects of local compositional and interface geometry on lateral cartilage repair integration by coupling microscale Raman spectroscopy and confocal elastography to measure tissue strains under compressive and shear loading. Histological integration assessments did not have significant relationships with interface strains under compressive loading (p > 0.083) and only the perimeter attachment score was trending towards statistical significance with the |Exy| strain tensor under shear loading (p = 0.050). Interface slope had a stronger correlation with local tissue strains under compressive and shear loading compared to compositional measures of GAG, collagen, or proteins (compressive loading |Eyy| tensor: R2 = 0.400 (interface slope), 0.005 (GAG), 0.024 (collagen), and 0.012 (protein); shear loading |Exy| tensor: R2 = 0.457 (interface slope), 0.003 (GAG), 0.006 (collagen), and 0.000 (total protein)). These data support surgical publications detailing the need for vertical walls when debriding chondral defects. Current histological integration assessments and local compositional measures were insufficient for identifying the variation in interface strains under compressive and shear loading. Thus, our data points to the importance of controlling interface geometry at the time of surgery, which has implications for cartilage repair integration and long-term healing.

Activation of astrocytic sigma-1 receptor exerts antidepressant-like effect via facilitating CD38-driven mitochondria transfer.

Despite sigma-1 receptor (Sig-1R) is a promising therapeutic target in depression, little is known regarding the cellular mechanisms underlying its antidepressant responses. Here, we demonstrated that astrocyte can be a direct cellular target of Sig-1R exerting antidepressant-like effect. In multiple behavioral models including forced swimming test (FST), tail suspension test (TST), open field test (OFT), and chronic unpredictable mild stress (CUMS), inhibition of astrocyte function blocked pharmacological Sig-1R activation-induced antidepressant-like effect, while specific activation of astrocytc Sig-1R by adeno-associated virus (AAV) was sufficient to produce antidepressant-like effect. In depression-related cellular tests, Sig-1R agonist or lentivirus-stimulated astrocyte conditioned medium (ACM) promoted neuronal neurite outgrowth, dendritic branch, and survival. Mechanismly, stimulation of Sig-1R enhanced the expression of CD38 via activation of extracellular regulated protein kinases 1/2 (ERK1/2), resulting in facilitating mitochondrial transfer from astrocyte. Furthermore, blockage of CD38-driven astrocyte transferring mitochondria in vivo and in vitro reversed the antidepressant-like effect of pharmacological Sig-1R activation. Thus, this study sheds light on the cellular mechanism of Sig-1R activation producing antidepressant-like effect. These data present the first evidence that enhancement of Sig-1R action on astrocytes entirely exerts antidepressant-like effect, indicating that specific activation of astrocytic Sig-1R may provide a new approach for antidepressant drug development.

Electrochromatographic behavior of core-shell particles: A comparison study.

Core-shell particle is a new generation high performance packing material for liquid chromatography. Through comparison with a classical totally porous silica phase of the same particle size, we studied Ascentis Express 5 µm core-shell particle's electrochromatographic behavior, in terms of voltage-current property, electroosmotic flow (EOF) and van Deemter curve. It was found, due to the nonpermeable solid core, the core-shell particle presented a diminished EOF and efficiency than the totally porous paricle. This on the other hand proved that the intra-particle pore flow extensively exists and plays an important role in electrochromatography on totally porous material. The core-shell particle's high retentivity led to an enhanced resolution for weakly retained hydrophilic peptides, which were poorly retained and co-eluted on totally porous particles. Further exploration has shown the core-shell material can achieve efficient electrochromatography of protein digests, excellent performance in terms of resolution, reproducibility and long term stability have been observed. The results indicate that the core-shell structure may suggest a reasonable design of stationary phase for bioelectrochromatography of peptides and proteins.

Heterogeneous reaction of peroxyacetyl nitrate (PAN) on soot.

The interaction between photochemical oxidants and aerosol particles has been examined in previous atmospheric pollution studies. The heterogeneous reaction can affect the concentration of gases and free radicals, as well as the morphology and properties of particles. In this report, the interaction between the photochemical oxidant peroxyacetyl nitrate (PAN) and soot particles was investigated using a flow tube system. We used real-time online monitoring equipment to track changes in PAN concentrations. Substances on the soot surface were detected using ion chromatography (IC), x-ray photoelectron spectroscopy (XPS), and other surface analysis methods. At 295 K, the upper and lower limits of the initial uptake coefficients were 1.28 × 10-5 and 9.16 × 10-9, respectively. The heterogeneous reaction of PAN on soot was a first-order reaction to PAN under both dry and wet conditions. The products formed on soot included CH3COO-, HCOO-, NO2-, and NO3-. With an increase in relative humidity, the production of all species decreased and the relative amounts changed.

Involvement of EGF receptor signaling and NLRP12 inflammasome in fine particulate matter-induced lung inflammation in mice.

Epidemiological studies have shown that exposure to ambient fine particulate matter (PM2.5 ) is associated with respiratory diseases. Lung inflammation is a central feature of many pulmonary diseases, which can be induced by PM2.5 exposure. However, the mechanisms underlying PM2.5 -induced lung inflammation remain unclear. To characterize the role of epidermal growth factor receptor (EGFR) and inflammasome in PM2.5 -induced lung inflammation in mice, 30 BALB/c mice were intrabroncheally instilled with saline and PM2.5 suspension (4.0 mg/kg b.w.) for 5 consecutive days, respectively. Bronchoalveolar lavage (BAL) was conducted and BAL fluid (BALF) was collected. The levels of reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), epidermal growth factor (EGF), CXCL1, interleukin (IL)-1ß, and IL-18 in BALF were determined using ELISA. mRNA levels of IL-6, IL-1ß, IL-18, CXCL1, IL-10, NLRP3, Caspase-1, and NLRP12 in lung tissues were determined by RT-PCR. Phospho-EGFR (Tyr1068) and phospho-Akt (Thr308) in lung tissues were examined using immunohistochemical staining and Western blotting, respectively. Protein levels of Caspase-1, NLRP3, NF-κB-p52/p100, and NF-κB-p65 in bronchial epithelium were examined using immunohistochemical staining. It was shown that PM2.5 exposure induced lung inflammation. Levels of total protein, ROS, iNOS, EGF, and CXCL1 and cell number in the BALF of mice exposed to PM2.5 were markedly elevated relative to the control. mRNA levels of CXCL1, IL-1ß, and IL-18 in lung tissues of PM2.5 -exposed mice were increased in comparison with the control. However, level of NLRP12 mRNA in lung tissues of PM2.5 -exposed mice was reduced. Phospho-EGFR (Tyr1068) and phospho-Akt (Thr308) levels in the lungs of PM2.5 -instilled mice were higher than those in the lungs of the control. The protein levels of NF-κB-p52/p100 and NF-κB-p65 in bronchial epithelium of PM2.5 -exposed mice were also increased compared with the control. This study suggests that EGF-EGFR-Akt-NF-κB signaling and NLRP12 inflammasome may be associated with PM2.5 -induced lung inflammation in mice. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1121-1134, 2017.