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ObjectivesThe objective of this study was to profile the transcriptional profiles of peripheral blood mononuclear cells (PBMCs) and their immune repertoires affected by anti-synthetase syndrome (ASS) at the single-cell level.MethodsWe performed single-cell RNA sequencing (scRNA-seq) analysis of PBMCs and bulk RNA sequencing for patients with ASS (N=3) and patients with anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+ DM, N=3) along with healthy controls (HCs, N=4). As ASS and MDA5+ DM have similar organ involvements, MDA5+ DM was used as a disease control. The immune repertoire was constructed by reusing the same scRNA-seq datasets. Importantly, flow cytometry was performed to verify the results from the scRNA-seq analysis.ResultsAfter meticulous annotation of PBMCs, we noticed a significant decrease in the proportion of mucosal-associated invariant T (MAIT) cells in ASS patients compared to HCs, while there was a notable increase in the proportion of proliferative NKT cells. Compared with MDA5+ DM patients, in their PBMCs ASS patients presented substantial enrichment of interferon pathways, which were primarily mediated by IFN-II, and displayed a weak immune response. Furthermore, ASS patients exhibited more pronounced metabolic abnormalities, which may in turn affect oxidative phosphorylation pathways. Monocytes from ASS patients appear to play a crucial role as receptive signaling cells for the TNF pathway. Immunophenotyping analysis of PBMCs from ASS patients revealed an increasing trend for the clone type CQQSYSTPWTF.ConclusionUsing single-cell genomic datasets of ASS PBMCs, we revealed a distinctive profile in the immune system of individuals with ASS, compared to that with MDA5+ DM or healthy controls.

BackgroundTo explore the relationship between serum levels of inflammatory markers and symptomatic severity of bipolar disorder (BD).Materials and methodsA cross-sectional study was conducted on 126 BD patients with current depressive episode (BDD), 102 BD patients with current mixed or (hypo)manic episode (BDM) and 94 healthy controls (HC). All participants were drug-naïve and had no current active physical illness associated with inflammatory response or history of substance abuse. Fasting serum levels of CRP, leptin (LEP), adiponectin (ADP), visfatin (VIS), TNF-α, IL-2, IL-6, IL-10, IL-17), and monocyte chemoattractant protein-1 (MCP-1) were measured with enzyme-linked immunosorbent assay (ELISA). Symptomatic severity of BD was assessed with HAMD-17 and YMRS. Generalized linear model was used to determine the association between the serum levels of inflammatory markers and symptomatic severity of BD.ResultsThe serum levels of IL-6, IL-10 and IL-17, and the IL-6/IL-10 ratio were significantly lower in mild BDD than in HC. In moderate BDD, the serum levels of MCP, IL-6 and IL-17 were significantly lower than in HC. In severe BDD, the serum level of ADP, MCP-1, IL-10 and IL-17and the IL-17/IL-10 ratio were significantly lower than in HC. The serum levels of TNF-α and the IL-6/IL-10 ratio were significantly higher in mild BDM than in HC. In moderate BDM, the serum level of VIS, IL-2, and IL-17 were significantly higher than in HC, but the IL-6/IL-10 ratio was significantly lower than in control. In severe BDM, the serum levels of IL-6 and IL-17 and the ratios of IL-6/IL-10 and IL-17/IL-10 were significantly lower than in HC, but the neutrophil/lymphocyte ratio was significantly higher than in HC.ConclusionIn BDD, immune-inhibition is persistently predominant, while in mild-to-moderate BDM, immune system is activated but inhibited in severe BDM. The dynamic change of serum inflammatory markers suggests that alteration of peripheral inflammatory markers in BD is state-dependent instead of trait-marked.

Objective: To investigate the neuroprotective effects of trihydroxyethyl rutin in rats with cervical spinal cord hemi-contusion.Methods: Adult male Sprague–Dawley rats were subjected to hemi-contusion at a stroke depth of 1.2 mm, and then intraperitoneally injected with 50 or 100 mg/kg trihydroxyethyl rutin per day for 12 weeks (T50 and T100 groups, respectively). Changes in somatosensory evoked potentials (SEPs), motor evoked potentials (MEPs), and behavior were continuously monitored. At 12 weeks post-injury, immunohistochemical staining was performed to assess changes in cervical spinal cord microvascular morphology. Magnetic resonance imaging (MRI) scans were performed to examine end-stage injury in the cervical spinal cord, and Eriochrome cyanine-stained slices of spinal cord tissue were evaluated for injury.Results: There were no significant differences in biomechanical parameters among the spinal cord injury, T50 and T100 rat groups. At 3 days-post-injury, there was a significant decrease in grip strength. At 12 weeks post-injury, grip strength recovery was significantly better in the T50 and T100 groups than in the injury group. Compared with the injury group, the total limb placement frequency was significantly higher in the T50 group at 2, 4, 6, 10, and 12 weeks post-injury and in the T100 group at 2, 6, 8, and 10 weeks post-injury. Ipsilateral SEPs and MEPs were dynamic, increasing in latency and decreasing in amplitude in the injury compared with sham group. MRI scanning demonstrated that the coronal, sagittal, and transversal lesion areas were smaller in the T50 and T100 groups than in the injury group. Microvascular density showed a greater reduction in the injury group compared with the T50 and T100 groups. Eriochrome cyanine staining showed that the ipsilateral side, residual parenchyma, and gray matter areas were larger in the T50 and T100 groups than in the injury group.Conclusion: Trihydroxyethyl rutin exhibits robust neuroprotective effects, improving limb motor function and nerve electrophysiological parameters after spinal cord injury, maintaining microvascular density, and reducing the area of injury and degree of demyelination.

Background: Medication non-adherence is prevalent in patients with bipolar disorder (BD). Long-acting injectable antipsychotics (LAIAs) are widely used to improve compliance with treatment. This study aimed to illustrate the effectiveness, compliance, and safety profile of once-monthly paliperidone palmitate (PP1M), a novel therapeutic LAIA, in the management of bipolar I disorder (BDI).Method: A prospective follow-up was arranged to 11 BDI patients who were prescribed PP1M as monotherapy or adjunctive treatment. Severity of symptoms, disturbing behavior, status of employment, 17-item Hamilton Depression Rating Scale (HAMD-17), and Young Mania Rating Scale (YMRS) were evaluated at the baseline and the endpoint of follow-up. Clinical Global Impression—Bipolar Disorder—Severity of Illness Scale (CGI-BP) and Treatment Emergent Symptom Scale (TESS) were measured at each injection of PP1M. Compliance, relapse or switch, and new hospitalization were monitored through the period of follow-up.Results: The median duration of treatment was 14 months, ranging from 5 to 22 months. The scores (mean ± standard deviation) of HAMD-17, YMRS, and CGI-BP generally decreased from the baseline (16.1 ± 10.3, 30.9 ± 12.6, 5.3 ± 0.7) to the endpoint (7.4 ± 5.7, 3.7 ± 3.2, 2.3 ± 0.7). No disturbing behavior was detected at the endpoint. Neither new hospitalization nor manic/mixed episode occurred during treatment, whereas mild to moderate depressive episodes were reported in three cases. The status of employment of 10 participants (90.9%) was improved, and no new safety concern was detected.Conclusion: PP1M might offer a new valid treatment option in the long-term management of BDI, especially for those with poor compliance with oral medication. However, more studies are needed to further justify such role.

Protecting white matter is one of the key treatment strategies for spinal cord injury (SCI), including alleviation of myelin loss and promotion of remyelination. Rapamycin has been shown neuroprotective effects against SCI and cardiotoxic effects while enhancing autophagy. However, specific neuroprotection of rapamycin for the white matter after cervical SCI has not been reported. Therefore, we aim to evaluate the role of rapamycin in neuroprotection after hemi-contusion SCI in mice. Forty-six 8-week-old mice were randomly assigned into the rapamycin group (n = 16), vehicle group (n = 16), and sham group (n = 10). All mice of the rapamycin and vehicle groups received a unilateral contusion with 1.2-mm displacement at C5 followed by daily intraperitoneal injection of rapamycin or dimethyl sulfoxide solution (1.5 mg⋅kg–1⋅day–1). The behavioral assessment was conducted before the injury, 3 days and every 2 weeks post-injury (WPI). The autophagy-related proteins, the area of spared white matter, the number of oligodendrocytes (OLs) and axons were evaluated at 12 WPI, as well as the glial scar and the myelin sheaths formed by Schwann cells at the epicenter. The 1.2 mm contusion led to a consistent moderate–severe SCI in terms of motor function and tissue damage. Rapamycin administration promoted autophagy in spinal cord tissue after injury and reduced the glial scar at the epicenter. Additionally, rapamycin increased the number of OLs and improved motor function significantly than in the vehicle group. Furthermore, the rapamycin injection resulted in an increase of Schwann cell-mediated remyelination and weight loss. Our results suggest that rapamycin can enhance autophagy, promote Schwann cell myelination and motor function recovery by preserved neural tissue, and reduce glial scar after hemi-contusive cervical SCI, indicating a potential strategy for SCI treatment.

Suilysin (SLY) plays a critical role in Streptococcus suis infections making it an ideal target to the combat infection caused by this pathogen. In the present study, we found that piceatannol (PN), a natural compound, inhibits pore-formation by blocking the oligomerization of SLY without affecting the growth of S. suis and the expression of SLY. Furthermore, PN alleviated the J774 cell damage and the expression of the inflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-1α (IL-1β) induced by S. suis in vitro. The computational biology and biochemistry results indicated that PN binds to the joint region of D2 and D4 in SLY, and Asn57, Pro58, Pro59, Glu76, Ile379, Glu380, and Glu418 were critical residues involved in the binding. The binding effect between PN and SLY hindered the SLY monomers from forming the oligomers, thereby weakening the hemolytic activity of SLY. This mechanism was also verified by hemolysis analysis and analysis of KA formation after site-specific mutagenesis. Furthermore, PN protected mice from S. suis infections by reducing bacterial colony formation and the inflammatory response in target organs in vivo. These results indicate that PN is a feasible drug candidate to combat S. suis infections.

ObjectiveTo investigate the effects of ketogenic metabolism on macrophage polarization, inflammation inhibition, and function recovery after acute spinal cord injury (SCI) in rats.MethodsSixty-four adult male Sprague–Dawley rats were randomly and equally divided into sham, standard diet (SD), ketone diet (KD), and 1, 3-butanediol (BD) groups. All animals underwent C5 unilateral laminectomy, whereas the SD, KD, and BD groups underwent C5 spinal cord hemi-contusion. The impact rod with a diameter of 1.5 mm was aligned 22.5° to the left and 1.4 mm to the midline, and then triggered to deliver a set displacement of 1.5 mm at a speed of 100 mm/s. The gene expression of inflammatory factors as well as the protein expression of inducible nitric oxide synthase, arginase-1, and inflammatory factors were measured at 1 week post-injury. Serum ketone and behavior were evaluated every second week for 12 weeks. Then, histological analyses of the gray and white matter at the epicenter were conducted at 12 weeks post-injury.ResultsThe serum ketone levels of the KD and BD groups were significantly increased when compared with the SD group. The gene and protein expression of TNF-α and IL-1β tended to increase after the SCI, but were inhibited in the KD and BD groups. The protein expression of inducible nitric oxide synthase, marker of M1 macrophage, was inhibited in the KD and BD groups; on the other hand, the expression of arginase-1, marker of M2 macrophage, was boosted in the KD and BD groups. The usage of the ipsilateral forelimb was higher in the KD group than in the SD group. The hemi-contusive injury resulted in an obvious ipsilateral lesion area at the epicenter, and there was no significant difference between groups regarding the lesion size. However, the spared gray matter area was significantly greater in the KD group than in the SD and BD groups.ConclusionThe present study suggests that ketogenic metabolism promotes macrophage polarization to M2, inhibits an inflammatory response, and alleviates the loss of gray matter after SCI. A higher ketone level, such as that induced by the ketogenic diet, seems to benefit function recovery after SCI.

Background: Liver injury commonly occurs in patients with COVID-19. There is limited data describing the course of liver injury occurrence in patients with different disease severity, and the causes and risk factors are unknown. We aim to investigate the incidence, characteristics, risk factors, and clinical outcomes of liver injury in patients with COVID-19.Methods: This retrospective observational study was conducted in three hospitals (Zhejiang, China). From January 19, 2020 to February 20, 2020, patients confirmed with COVID-19 (≥18 years) and without liver injury were enrolled and divided into non-critically ill and critically ill groups. The incidence and characteristics of liver injury were compared between the two groups. Demographics, clinical characteristics, treatments, and treatment outcomes between patients with or without liver injury were compared within each group. The multivariable logistic regression model was used to explore the risk factors for liver injury.Results: The mean age of 131 enrolled patients was 51.2 years (standard deviation [SD]: 16.1 years), and 70 (53.4%) patients were male. A total of 76 patients developed liver injury (mild, 40.5%; moderate, 15.3%; severe, 2.3%) with a median occurrence time of 10.0 days. Critically ill patients had higher and earlier occurrence (81.5 vs. 51.9%, 12.0 vs. 5.0 days; p < 0.001), greater injury severity (p < 0.001), and slower recovery (50.0 vs. 61.1%) of liver function than non-critically ill patients. Multivariable regression showed that the number of concomitant medications (odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.05–1.21) and the combination treatment of lopinavir/ritonavir and arbidol (OR: 3.58, 95% CI: 1.44–9.52) were risk factors for liver injury in non-critically ill patients. The metabolism of arbidol can be significantly inhibited by lopinavir/ritonavir in vitro (p < 0.005), which may be the underlying cause of drug-related liver injury. Liver injury was related to increased length of hospital stay (mean difference [MD]: 3.2, 95% CI: 1.3–5.2) and viral shedding duration (MD: 3.0, 95% CI: 1.0–4.9).Conclusions: Critically ill patients with COVID-19 suffered earlier occurrence, greater injury severity, and slower recovery from liver injury than non-critically ill patients. Drug factors were related to liver injury in non-critically ill patients. Liver injury was related to prolonged hospital stay and viral shedding duration in patients with COVID-19.Clinical Trial Registration: World Health Organization International Clinical Trials Registry Platform, ChiCTR2000030593. Registered March 8, 2020.

Background: To explore the relationship between serum levels of inflammatory markers and symptomatic severity of bipolar disorder (BD). Materials and methods: A cross-sectional study was conducted on 126 BD patients with current depressive episode (BDD), 102 BD patients with current mixed or (hypo)manic episode (BDM) and 94 healthy controls (HC). All participants were drug-naïve and had no current active physical illness associated with inflammatory response or history of substance abuse. Fasting serum levels of CRP, leptin (LEP), adiponectin (ADP), visfatin (VIS), TNF-α, IL-2, IL-6, IL-10, IL-17), and monocyte chemoattractant protein-1 (MCP-1) were measured with enzyme-linked immunosorbent assay (ELISA). Symptomatic severity of BD was assessed with HAMD-17 and YMRS. Generalized linear model was used to determine the association between the serum levels of inflammatory markers and symptomatic severity of BD. Results: The serum levels of IL-6, IL-10 and IL-17, and the IL-6/IL-10 ratio were significantly lower in mild BDD than in HC. In moderate BDD, the serum levels of MCP, IL-6 and IL-17 were significantly lower than in HC. In severe BDD, the serum level of ADP, MCP-1, IL-10 and IL-17and the IL-17/IL-10 ratio were significantly lower than in HC. The serum levels of TNF-α and the IL-6/IL-10 ratio were significantly higher in mild BDM than in HC. In moderate BDM, the serum level of VIS, IL-2, and IL-17 were significantly higher than in HC, but the IL-6/IL-10 ratio was significantly lower than in control. In severe BDM, the serum levels of IL-6 and IL-17 and the ratios of IL-6/IL-10 and IL-17/IL-10 were significantly lower than in HC, but the neutrophil/lymphocyte ratio was significantly higher than in HC. Conclusion: In BDD, immune-inhibition is persistently predominant, while in mild-to-moderate BDM, immune system is activated but inhibited in severe BDM. The dynamic change of serum inflammatory markers suggests that alteration of peripheral inflammatory markers in BD is state-dependent instead of trait-marked. [ABSTRACT FROM AUTHOR]