Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite.

Tumors employ various strategies to evade immune surveillance. Central nervous system (CNS) has multiple features to restrain immune response. Whether tumors and CNS share similar programs of immunosuppression is elusive. Here, we analyze multi-omics data of tumors from HER2+ breast cancer patients receiving trastuzumab and anti-PD-L1 antibody and find that CNS-enriched N-acetyltransferase 8-like (NAT8L) and its metabolite N-acetylaspartate (NAA) are overexpressed in resistant tumors. In CNS, NAA is released during brain inflammation. NAT8L attenuates brain inflammation and impairs anti-tumor immunity by inhibiting cytotoxicity of natural killer (NK) cells and CD8+ T cells via NAA. NAA disrupts the formation of immunological synapse by promoting PCAF-induced acetylation of lamin A-K542, which inhibits the integration between lamin A and SUN2 and impairs polarization of lytic granules. We uncover that tumor cells mimic the anti-inflammatory mechanism of CNS to evade anti-tumor immunity and NAT8L is a potential target to enhance efficacy of anti-cancer agents.

Biomimetic protein structural transitions regulate activation and inhibition of the broad-spectrum bactericidal activity of cationic nanoparticles.

The development of cationic polymers as alternative materials to antibiotics necessitates addressing the challenge of balancing their antimicrobial activity and toxicity. Here we propose a precise switching strategy inspired by biomimetic voltage-gated ion channels, enabling controlled activation and inhibition of cationic antimicrobial functions through protein conformational transitions in diverse physiological environments. Following thermodynamic studies on the specific recognition between mannose end groups on polycations and concanavalin A (ConA), we synthesized a type of ConA-polycation nanoparticle. The nanoparticle was inhibited under neutral conditions, with cationic moieties shielded by ConA's ß-sheet. This shielding suppresses their antimicrobial activity, thereby ensuring satisfactory biocompatibility. In mildly acidic environments, however, the transition of a portion of ConA to an α-helix conformation exposed cations at the particle periphery, activating antibacterial functionality. Compared to inhibited nanoparticles, those in the activated state exhibited a 32-256 times reduction in the minimum bactericidal concentration against bacteria and fungi (2-16 µg/mL). In a murine acute pulmonary infection model, intravenous administration of inhibited nanoparticles effectively reduced bacterial counts by 4-log within 12 h. The biomimetic design, regulating cationic antimicrobial functionality through the alteration in protein secondary structure, significantly retards bacterial resistance development, holding great promise for intelligent antimicrobial materials. STATEMENT OF SIGNIFICANCE: Cationic antimicrobial polymers exhibit advantages distinct from antibiotics due to their lower propensity for resistance development. However, the presence of cationic moieties also poses a threat to healthy cells and tissues, significantly constraining their potential for clinical applications. To address this challenge, we propose a biomimetic strategy that mimics voltage-gated ion channels to activate the antimicrobial functionality of cations selectively in bacterial environments through the conformational transitions of proteins between ß-sheets and α-helices. In healthy tissues, the antimicrobial functionality is inhibited, ensuring satisfactory biocompatibility. Antimicrobial cationic materials capable of intelligent switching between an activated state and an inhibited state in response to environmental changes offer an effective strategy to prevent the development of resistance and mitigate potential side effects.

Use of Tox21 screening data to profile PFAS bioactivities on nuclear receptors, cellular stress pathways, and cytochrome p450 enzymes.

Per- and poly-fluoroalkyl substances (PFAS) are synthetic chemicals widely used in commercial products. PFAS are a global concern due to their persistence in the environment and extensive associations with adverse health outcomes. While legacy PFAS have been extensively studied, many non-legacy PFAS lack sufficient toxicity information. In this study, we first analyzed the bioactivity of PFAS using Tox21 screening data surveying more than 75 assay endpoints (e.g., nuclear receptors, stress response, and metabolism) to understand the toxicity of non-legacy PFAS and investigate potential new targets of PFAS. From the Tox21 screening data analysis, we confirmed several known PFAS targets/pathways and identified several potential novel targets/pathways of PFAS. To confirm the effect of PFAS on these novel targets/pathways, we conducted several cell- and enzyme-based assays in the follow-up studies. We found PFAS inhibited cytochromes P450s (CYPs), especially CYP2C9 with IC50 values of < 1 µM. Considering PFAS affected other targets/pathways at > 10 µM, PFAS have a higher affinity to CYP2C9. This PFAS-CYP2C9 interaction was further investigated using molecular docking analysis. The result suggested that PFAS directly bind to the active sites of CYP2C9. These findings have important implications to understand the mechanism of PFAS action and toxicity.

Polymer Network Film with Double Reflection Bands Prepared Using a Thermochromic Cholesteric Liquid Crystal Mixture.

Cholesteric liquid crystal polymer network (CLCN) films with a single reflection band have found applications for decoration and anticounterfeiting. The CLCN films with double reflection bands were more suitable for these applications. Herein, they were prepared by using thermochromic cholesteric liquid crystals (CLCs) through a two-step photopolymerization approach. At the first step, due to oxygen inhibition, the CLC monomers near the substrate surface were polymerized at a certain temperature. At the second step, those near the air were polymerized at another temperature. The wavelengths of these two reflection bands of the CLCN film were dominated by the two polymerization temperatures. Based on this approach, patterns with composite colors were prepared, which were suitably applied for decoration. Moreover, a double-layered CLCN film with a broad reflection band was prepared that could potentially be applied for displays.

Sequential neoadjuvant chemotherapy using pegylated liposomal doxorubicin and cyclophosphamide followed by taxanes with complete trastuzumab and pertuzumab treatment for HER2-positive breast cancer: A phase II single-arm study.

Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin (PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2 (HER2)-positive early breast cancer (BC). Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD (30-35 mg/m2) and cyclophosphamide (600 mg/m2), followed by four cycles of taxanes (docetaxel, 90-100 mg/m2 or nab-paclitaxel, 260 mg/m2), concomitant with eight cycles of trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0). Secondary endpoints included breast pCR (bpCR), objective response rate (ORR), disease control rate, rate of breast-conserving surgery (BCS), and safety (with a focus on cardiotoxicity). Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42 (53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval (95% CI), 48.5%-71.2%] patients achieved tpCR, and 49 (62.8%) achieved bpCR. ORRs were 76.9% (95% CI, 66.0%-85.7%) and 93.6% (95% CI, 85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine (11.5%) patients experienced asymptomatic left ventricular ejection fraction (LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP (NT-proBNP), troponin I, or high-sensitivity troponin. Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile, especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.

Circularly Polarized Luminescence of Cholesteric Liquid Crystal Polymer Networks with a Europium(III) Complex as an Emitter.

A coordination complex, Eu(C12C12dbm)3(phen), with strong emission and a high quantum yield (QY ∼ 51.9%) was synthesized. The EuIII complex, as a fluorescent emitter, was embedded in cholesteric liquid crystal polymer networks (CLCNs). A series of free-standing EuIII-CLCN films were obtained, generating a typical sharp emission band corresponding to the EuIII complex. Tunable handedness of circularly polarized luminescence (CPL) with high |glum| values (up to 0.63) was observed. A series of CPL-active CLCN-coated PET films were also prepared (|glum| values up to 0.63), which can be used for large-area preparations. Moreover, by stacking an emitter-embedded PMMA layer and a CLCN layer, a composite system was built, and a large |glum| value (∼1.42) was achieved. Fluorescence patterns were prepared, and distinct images of CLCN films were recognized under both daylight and UV light. This work not only demonstrated that coordination compounds could be incorporated with CLCN films to prepare CPL-active materials with high |glum| values but also provided a new perspective for emissive CLCN materials used for anticounterfeiting and encryption.

Effectiveness of a broad-spectrum bivalent mRNA vaccine against SARS-CoV-2 variants in preclinical studies.

Vaccines utilizing modified messenger RNA (mRNA) technology have shown robust protective efficacy against SARS-CoV-2 in humans. As the virus continues to evolve in both human and non-human hosts, risk remains that the performance of the vaccines can be compromised by new variants with strong immune escape abilities. Here we present preclinical characterizations of a novel bivalent mRNA vaccine RQ3025 for its safety and effectiveness in animal models. The mRNA sequence of the vaccine is designed to incorporate common mutations on the SARS-CoV-2 spike protein that have been discovered along the evolutionary paths of different variants. Broad-spectrum, high-titer neutralizing antibodies against multiple variants were induced in mice (BALB/c and K18-hACE2), hamsters and rats upon injections of RQ3025, demonstrating advantages over the monovalent mRNA vaccines. Effectiveness in protection against several newly emerged variants is also evident in RQ3025-vaccinated rats. Analysis of splenocytes derived cytokines in BALB/c mice suggested that a Th1-biased cellular immune response was induced by RQ3025. Histological analysis of multiple organs in rats following injection of a high dose of RQ3025 showed no evidence of pathological changes. This study proves the safety and effectiveness of RQ3025 as a broad-spectrum vaccine against SARS-CoV-2 variants in animal models and lays the foundation for its potential clinical application in the future.

Cadmium Exposure Induces Apoptosis and Necrosis of Thyroid Cells via the Regulation of miR-494-3p/PTEN Axis.

Cadmium (Cd) exposure is a persistent pollution problem, necessitating caution in using cadmium-expelling complexing agents. Currently, there is no targeted therapy to treat Cd poisoning. The thyroid gland is a major endocrine organ that directly regulates thyroid hormones involved in various physiological processes and is a target organ for Cd accumulation. Herein, the effects of Cd exposure on swine thyroid glands were investigated. Six-week-old male pigs were randomly divided into the Cd and control groups. The control group was fed a normal diet containing 0 mg Cd/kg, while the Cd group was fed a diet containing 20 mg Cd/kg (CdCl2) for 40 days. The regulation mechanism of phosphatase and tensin homolog (PTEN) microRNA-494-3p (miR-494-3p) was evaluated to determine the toxic effects of Cd exposure on free radicals' cleaner. Notably, heat shock proteins (HSPs) were triggered as defense agents against Cd. Cd exposure increased the enzyme activity of superoxide dismutase1(SOD1) and SOD2, catalase (CAT), and glutathione (GSH), and the endoplasmic reticulum stress in thyroid cells. Histopathological staining, RT-qPCR, and Western Blot assays were further employed to detect possible apoptosis and necroptosis of thyroid cells induced by Cd exposure. The assays revealed increased thyroid inflammatory injury, fibrosis, and apoptosis caused by Cd exposure. This study demonstrates the role of microRNAs in regulating Cd toxicity in pig thyroid tissue and provides evidence of Cd's negative effects. It further provides an assessment of the toxicological impact of Cd as an environmental endocrine disruptor (ED) that threatens public health and safety, which forms a basis for the development of Cd poisoning treatment therapies.

Capturing Protein-Protein Interactions with Acidic Amino Acids Reactive Cross-Linkers.

Acidic residues (Asp and Glu) have a high prevalence on protein surfaces, but cross-linking reactions targeting these residues are limited. Existing methods either require high-concentration coupling reagents or have low structural compatibility. Here a previously reported "plant-and-cast" strategy is extended to develop heterobifunctional cross-linkers. These cross-linkers first react rapidly with Lys sidechains and then react with Asp and Glu sidechains, in a proximity-enhanced fashion. The cross-linking reaction proceeds at neutral pH and room temperature without coupling reagents. The efficiency and robustness of cross-linking using model proteins, ranging from small monomeric proteins to large protein complexes are demonstrated. Importantly, it is shown that this type of cross-linkers are efficient at identifying protein-protein interactions involving acidic domains. The Cross-linking mass spectrometry (XL-MS) study with p53 identified 87 putative binders of the C-terminal domain of p53. Among them, SARNP, ZRAB2, and WBP11 are shown to regulate the expression and alternative splicing of p53 target genes. Thus, these carboxylate-reactive cross-linkers will further expand the power of XL-MS in the analysis of protein structures and protein-protein interactions.

Preclinical evaluation of RQ3013, a broad-spectrum mRNA vaccine against SARS-CoV-2 variants.

The global emergence of SARS-CoV-2 variants has led to increasing breakthrough infections in vaccinated populations, calling for an urgent need to develop more effective and broad-spectrum vaccines to combat COVID-19. Here we report the preclinical development of RQ3013, an mRNA vaccine candidate intended to bring broad protection against SARS-CoV-2 variants of concern (VOCs). RQ3013, which contains pseudouridine-modified mRNAs formulated in lipid nanoparticles, encodes the spike (S) protein harboring a combination of mutations responsible for immune evasion of VOCs. Here we characterized the expressed S immunogen and evaluated the immunogenicity, efficacy, and safety of RQ3013 in various animal models. RQ3013 elicited robust immune responses in mice, hamsters, and nonhuman primates (NHP). It can induce high titers of antibodies with broad cross-neutralizing ability against the wild-type, B.1.1.7, B.1.351, B.1.617.2, and the newly emerging Omicron variants. In mice and NHP, two doses of RQ3013 protected the upper and lower respiratory tract against infection by SARS-CoV-2 and its variants. Furthermore, our safety assessment of RQ3013 in NHP showed no observable adverse effects. These results provide strong support for the evaluation of RQ3013 in clinical trials and suggest that it may be a promising candidate for broad protection against COVID-19 and its variants.

Polymer-Stabilized Cholesteric Liquid Crystal Films with Double Reflection Bands Prepared Based on the Competition between Photopolymerization and Photoisomerization.

Composite colors have been widely found in nature. Herein, polymer-stabilized cholesteric liquid crystal (PSCLC) films with composite structural colors were prepared through a one-step photopolymerization approach. The CLC mixtures were prepared using a mixture of acrylates and a mixture of two chiral dopants. One of the chiral dopants is polymerizable, and the other one is photoisomerizable. After photopolymerization, the PSCLC films with double Bragg reflection bands were obtained on the surface of a substrate. The competition between the photopolymerization of the acrylates and the photoisomerization of the chiral dopant was proposed to drive the formation of the double reflection bands. Without oxygen inhibition, the polymerization of the acrylates near the substrate surface was carried out. However, due to oxygen inhibition, the polymerization of the acrylates near the air was retarded. Then, the photoisomerization of the chiral dopant was carried out prior to the polymerization of the acrylates. The wavelengths of the double reflection bands were tunable by changing the concentrations of the acrylates and chiral dopants and the polymerization temperature. Colorful patterns with composite structural colors were prepared, which were suitable for decoration and anti-counterfeiting.

A PSCLC Pattern Prepared Based on Handedness Inversion for Anti-counterfeiting.

Handedness inversion has been widely studied in supramolecular chemistry and material sciences. Herein, a photoisomerizable chiral dopant was synthesized, which could induce the formation of a cholesteric phase with right-handedness. The Bragg reflection band of the cholesteric liquid crystal (CLC) mixture shifted to the long wavelength with extending 365 nm UV light irradiation time. Based on this photochromic property, a colourful polymer-stabilized CLC (PSCLC) film was prepared using a grayscale mask. A handedness reversible CLC mixture was prepared using a mixture of this chiral dopant and S5011. With extending the UV light irradiation time, the handedness of the CLC mixture changed from right- to left-handedness. A patterned PSCLC film was prepared using this CLC mixture. Complementary images were observed under right- and left-handedness circularly polarized lights. The results shown here not only give us a better understanding the competition between photopolymerization and photoisomerization, but also lay the foundations for decoration and anti-counterfeiting.

Precision Dosing of Antibiotics and Potentiators by Hypoxia-Responsive Nanoparticles for Overcoming Antibiotic Resistance in Gram-Negative Bacteria.

The stalling development of antibiotics, especially against intrinsically resistant Gram-negative pathogens associated with outer membranes, leads to an emerging antibiotic crisis across the globe. To breathe life into existing drugs, we herein report a hypoxia-responsive nanoparticle (NP) that encapsulates a hydrophobic antibiotic, rifampicin, and a cationic potentiator, polysulfonium. The simultaneous release of antibiotics and potentiators can be promoted and inhibited in response to the severity of bacterial-induced hypoxia, leading to antimicrobial dosing in a precision manner. Under the synergism of polysulfoniums with membrane-disruption capability, the NPs can intensively decrease the antibiotic dose by up to 66-95% in eliminating planktonic Gram-negative P. aeruginosa bacteria and achieve an 8-log reduction of bacteria in mature biofilms at rifampicin MIC. The NP formulation demonstrates that precision dosing of antibiotics and potentiators regulated by hypoxia provides a promising strategy to maximize efficacy and minimize toxicity in treating Gram-negative bacterial infection.

Transcriptomic analysis of ovarian follicles uncovers the crucial genes relevant to follicle selection and preovulatory hierarchy in hens.

Follicle selection and preovulatory hierarchy of hen ovaries were important stages of follicle development and crucially determining egg-laying performance. The selected follicles with a higher expression level of follicle-stimulating hormone receptor (FSHR) mRNA that facilitates response to FSH, and rapidly develops into preovulatory follicles with distinctive characteristics of granulosa cells (GCs) proliferation and differentiation. Identification of the key genes involved in these developmental events is helpful for elucidation of the molecular mechanism underlying egg-laying traits in chicken and other domestic fowl. Herein, the comparative transcriptomic analysis of ovarian prehierarchical follicles before selection (BSF), follicles at selection stage (ASF), and hierarchical follicles (HF) were implemented in the Jilin Black chicken (JB) and Lohmann Brown layer (LB) with the divergences in their egg-laying performance by RNA-sequencing. The results showed that nine deferentially expressed genes (DEGs), including STMN4, FABP3, ROBO2, RSPO4, and DMRT1 were revealed between follicles BSF and ASF; and seventeen DEGs, such as SLC6A15, SLITRK3, PRKG2 and TMC3 were mined between ASF and HF. These two group DEGs being co-expressed between BSF and ASF, and between ASF and HF were compared and substantiated in the JB and LB layers, respectively. Furthermore, 10 signaling pathways, such as cAMP signaling, PPAR signaling pathway, AMPK(Adenosine 5'-monophosphate (AMP)-activated protein kinase) pathway, and estrogen signaling pathway were also identified. Moreover, the roles of two representative candidates ROBO2 and PRKG2 genes presented as downregulated mRNA expression pattern in the transcriptomic profiles were further verified in vitro. The results demonstrated that downregulation of ROBO2 or PRKG2 significantly increased the expression levels of FSHR mRNA and protein with the boosted expression of CCND1, STAR, and BCL-2, whereas remarkably inhibited the expression of Caspase-3, consequently, brought about the decrease of GC apoptosis in the ovarian follicles, but increase of GC proliferation and differentiation serving as the hallmarks for follicle selection. It indicated that ROBO2 and PRKG2 may play indispensable roles in follicle selection and preovulatory hierarchy of hen ovaries separately. Our findings provided a comparative transcriptomic evidence for clarifying the molecular mechanism of the follicle development underlying egg-laying traits in chicken.

Chicken ovarian follicle development undergoes follicle recruitment, prehierarchy, follicle selection, preovulatory/hierarchy, and finally ovulation. The follicle selection and preovulatory hierarchy play a vital role in egg production of hens. However, underlying the mechanism of the key genes involved in these developmental events remains largely unknown. Herein, to explore the promising genes potentially involved in follicle selection and hierarchical development of hen ovary, a comparative transcriptome analysis of the ovarian follicles before and after selection was performed by using Jilin Black (JB) chicken, an indigenous Chinese breed with a low egg-laying rate and strong broodiness, and which was substantiated by using Lohmann Brown (LB) layer, a commercial egg-laying breed, being characterized by a high rate of egg production. As a result, a total of nine critical differentially expressed genes (DEGs) that co-expressed in the ovarian follicles before selection compared with follicles at selection stage (ASF), and 17 DEGs in the ASF follicles compared with hierarchical follicles that developed shortly after the time of follicle selection were identified in the JB hens as well as in the LB layers, respectively. Moreover, the exact roles of two representative candidates ROBO2 and PRKG2 of the DEGs were further verified in regulation of the follicular granulosa cell proliferation and differentiation which are the major characteristics of follicle selection. And 10 signaling pathways that implicated in follicle selection and hierarchy were also enriched. The objectives aim to provide molecular evidence for underlying the regulatory mechanism of follicle development and egg production in chicken.

Dietary Lactobacillus reuteri SL001 Improves Growth Performance, Health-Related Parameters, Intestinal Morphology and Microbiota of Broiler Chickens.

It was assumed that dietary inclusion of Lactobacillus reuteri SL001 isolated from the gastric contents of rabbits could act as an alternative to feed antibiotics to improve the growth performance of broiler chickens. We randomly assigned 360 one-day-old AA white-feathered chicks in three treatments: basal diet (control), basal diet plus zinc bacitracin (antibiotic), and basal diet plus L. reuteri SL001 (SL001) treatment. The results showed the total BW gain and average daily gain (ADG) of broilers in SL001 treatment increased significantly (p < 0.05, respectively) compared with the control group from day 0 to 42. Moreover, we observed higher levels of immune globulins in both the SL001 group and the antibiotic group. Total antioxidant capacity and levels of antioxidant factors were also significantly increased (p ≤ 0.05, respectively) in the SL001 treatment group, while the interleukin 6, interleukin 4, creatinine, uric acid, total cholesterol, triglyceride, VLDL, LDL and malondialdehyde were remarkably decreased (p < 0.05, respectively). In the ileum of SL001 treatment broilers, the height of villi and the ratio of villi height to crypt depth were significantly increased (p < 0.05). Meanwhile, the crypt depth reduced (p < 0.01) and the ratio of villi height to crypt depth increased (p < 0.05) in the jejunum compared to the control. The abundance of microbiota increased in the gut of broilers supplemented with SL001. Dietary SL001 significantly increased the relative abundance of Actinobacteria in the cecal contents of broilers (p < 0.01) at the phylum level. In conclusion, L. reuteri SL001 supplementation promotes the growth performance of broiler chickens and exhibits the potential application value in the industry of broiler feeding.

Identification of Potent and Selective Acetylcholinesterase/Butyrylcholinesterase Inhibitors by Virtual Screening.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) play important roles in human neurodegenerative disorders such as Alzheimer's disease. In this study, machine learning methods were applied to develop quantitative structure-activity relationship models for the prediction of novel AChE and BChE inhibitors based on data from quantitative high-throughput screening assays. The models were used to virtually screen an in-house collection of ∼360K compounds. The optimal models achieved good performance with area under the receiver operating characteristic curve values ranging from 0.83 ± 0.03 to 0.87 ± 0.01 for the prediction of AChE/BChE inhibition activity and selectivity. Experimental validation showed that the best-performing models increased the assay hit rate by several folds. We identified 88 novel AChE and 126 novel BChE inhibitors, 25% (AChE) and 53% (BChE) of which showed potent inhibitory effects (IC50 < 5 µM). In addition, structure-activity relationship analysis of the BChE inhibitors revealed scaffolds for chemistry design and optimization. In conclusion, machine learning models were shown to efficiently identify potent and selective inhibitors against AChE and BChE and novel structural series for further design and development of potential therapeutics against neurodegenerative disorders.

A multicenter, randomized, double-blind, duloxetine-controlled, non-inferiority trial of desvenlafaxine succinate extended-release in patients with major depressive disorder.

BACKGROUND: Desvenlafaxine and duloxetine are selective serotonin and norepinephrine reuptake inhibitors. Their efficacy has not been directly compared using statistical hypotheses. This study evaluated the non-inferiority of desvenlafaxine extended-release (XL) to duloxetine in patients with major depressive disorder (MDD). METHODS: In this study, 420 adult patients with moderate-to-severe MDD were enrolled and randomly assigned (1:1) to receive 50 mg (once daily [QD]) of desvenlafaxine XL (n = 212) or 60 mg QD of duloxetine (n = 208). The primary endpoint was evaluated using a non-inferiority comparison based on the change from baseline to 8 weeks in the 17-item Hamilton Depression Rating Scale (HAMD17) total score. Secondary endpoints and safety were evaluated. RESULTS: Least-squares mean change in HAM-D17 total score from baseline to 8 weeks was -15.3 (95% confidence interval [CI]: -17.73, -12.89) in the desvenlafaxine XL group and - 15.9 (95% CI, -18.44, -13.39) in the duloxetine group. The least-squares mean difference was 0.6 (95% CI: -0.48, 1.69), and the upper boundary of 95% CI was less than the non-inferiority margin (2.2). No significant between-treatment differences were found in most secondary efficacy endpoints. The incidence of the most common treatment-emergent adverse events (TEAEs) was lower for desvenlafaxine XL than for duloxetine for nausea (27.2% versus 48.8%) and dizziness (18.0% versus 28.8%). LIMITATIONS: A short-term non-inferiority study without a placebo arm. CONCLUSIONS: This study demonstrated that desvenlafaxine XL 50 mg QD was non-inferior to duloxetine 60 mg QD in efficacy in patients with MDD. Desvenlafaxine had a lower incidence of TEAEs than duloxetine did.

Low-dose ketamine inhibits neuronal apoptosis and neuroinflammation in PC12 cells via α7nAChR mediated TLR4/MAPK/NF-κB signaling pathway.

Ketamine is commonly used for sedation, analgesia and anesthetics. Much evidence has shown that it has an immune-regulatory effect. The cholinergic anti-inflammatory pathway mediated by α7nAChR is a prominent target of anti-inflammatory therapy. However, whether ketamine suppresses inflammatory levels in nerve cells by activating α7nAChR remains unknown. Lipopolysaccharide (LPS) was used to establish the neuroinflammation model in PC12 cells in vitro, and α7nAChR siRNA was transfected into PC12 cells 30 min before LPS to inhibit gene expression of α7nAChR. PC12 cells were stimulated with LPS for 24 h, and the indicators were detected at 2 h after GTS-21 and ketamine were added. The results showed that LPS increased the proportion of PC12 cells apoptosis, activated TLR4/MAPK/NF-κB signaling pathway, and increased the expression of interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). Ketamine reduced the ratio of early apoptosis and late apoptosis of PC12, inhibited the entry of P65 into the nucleus, decreased the activation of TLR4/MAPK/NF-κB and improved neuroinflammation. However, the ameliorating effects of ketamine on neuronal apoptosis and neuroinflammation were inhibited in the α7nAChRi group. This indicated that α7nAChR played a key role in the anti-inflammatory process of ketamine. Low-dose ketamine inhibited TLR4/MAPK/NF-κB by activating the α7nAChR-mediated cholinergic anti-inflammatory pathway, thereby producing the protective effect on neuronal apoptosis and neuroinflammation.

Mediating effects of psychological capital on the relationship between workplace violence and professional identity among nurses working in Chinese public psychiatric hospitals: a cross-sectional study.

OBJECTIVE: To examine the relationship between workplace violence (WPV) and professional identity among Chinese psychiatric nurses and the mediating effects of psychological capital (PsyCap) from this association. SETTING: Seven public tertiary psychiatric hospitals in Liaoning Province, China. PARTICIPANTS: A total of 952 psychiatric nurses were recruited for this study. Registered nurses who have been engaged in psychiatric nursing for more than 1 year were eligible as participants in this investigation. OUTCOME MEASURES: Questionnaires consisting of the Workplace Violence Scale, the Occupational Identity Scale, the Psychological Capital Questionnaire and a demographic data sheet were used to collect participant information. We used hierarchical multiple regression and asymptotic and resampling strategies to examine the mediating role of PsyCap in the relationship between WPV and professional identity. RESULTS: WPV was negatively associated with professional identity after controlling for demographic factors (ß=-0.353; p<0.001). PsyCap mediated the relationship between WPV and professional identity, according to the mediation analysis (a×b=-0.150, bias-corrected and accelerated 95% CI (BCa 95% CI) (-0.185 to -0.115); p<0.001). In addition, two dimensions of PsyCap: hope (a×b=-0.075, BCa 95% CI (-0.104 to -0.049); p<0.001) and resilience (a×b=-0.064, BCa 95% CI (-0.090 to -0.039); p<0.001) mediated the association between WPV and professional identity. For professional identity, hope, resilience and PsyCap mediation accounted for 21.6%, 18.1% and 42.4%, respectively. CONCLUSIONS: Based on these findings, PsyCap could partially mediate the relationship between WPV and professional identity. Therefore, hospital administrators should implement measures to prevent and reduce WPV and provide nurses with skills training programmes to improve the PsyCap such as hope and resilience.