Ketamine's rapid and sustained antidepressant effects are driven by distinct mechanisms.

Administration of multiple subanesthetic doses of ketamine increases the duration of antidepressant effects relative to a single ketamine dose, but the mechanisms mediating this sustained effect are unclear. Here, we demonstrate that ketamine's rapid and sustained effects on affective behavior are mediated by separate and temporally distinct mechanisms. The rapid effects of a single dose of ketamine result from increased activity of immature neurons in the hippocampal dentate gyrus without an increase in neurogenesis. Treatment with six doses of ketamine over two weeks doubled the duration of behavioral effects after the final ketamine injection. However, unlike ketamine's rapid effects, this more sustained behavioral effect did not correlate with increased immature neuron activity but instead correlated with increased numbers of calretinin-positive and doublecortin-positive immature neurons. This increase in neurogenesis was associated with a decrease in bone morphogenetic protein (BMP) signaling, a known inhibitor of neurogenesis. Injection of a BMP4-expressing lentivirus into the dentate gyrus maintained BMP signaling in the niche and blocked the sustained - but not the rapid - behavioral effects of ketamine, indicating that decreased BMP signaling is necessary for ketamine's sustained effects. Thus, although the rapid effects of ketamine result from increased activity of immature neurons in the dentate gyrus without requiring an increase in neurogenesis, ketamine's sustained effects require a decrease in BMP signaling and increased neurogenesis along with increased neuron activity. Understanding ketamine's dual mechanisms of action should help with the development of new rapid-acting therapies that also have safe, reliable, and sustained effects.

Stress hyperglycemia increases short-term mortality in acute ischemic stroke patients after mechanical thrombectomy.

BACKGROUND AND PURPOSE: Glucose-to-glycated hemoglobin ratio (GAR) is considered a more reliable marker of stress hyperglycemia by correcting for basal blood glucose levels. This study aimed to investigate the extent to which GAR is associated with 3 month and 1 year all-cause mortalities in patients with acute ischemic stroke (AIS) undergoing mechanical thrombectomy (MT). METHODS: We retrospectively followed 553 AIS patients who underwent MT. The degree of stress hyperglycemia was quantified as the GAR, defined as fasting plasma glucose (mmol/L)/hemoglobin A1c (HbA1c) (%) on the second day after admission. According to the GAR quartiles, the patients were further categorized into four groups (group 1-group 4). We assessed the association between GAR and all-cause mortalities, clinical outcomes during hospitalization and function outcomes at 3 months. The associations between stress hyperglycemia and all-cause mortalities were analyzed using a Cox proportional-hazards model, while other outcomes were analyzed using multiple logistic regression analysis. RESULTS: The follow-up lasted a median of 18 months (range 0-66 months). The 3 month mortality rate was 9.58% (n = 53) and the 1 year mortality rate was 18.62% (n = 103). The Kaplan-Meier analysis revealed a significant inverse relationship between GAR and mortality (P < 0.001). In the Cox proportional-hazards model at 3 months, compared with group1, group 4 of GAR was associated with a significant increase in the risk of 3 month mortality (hazard ratio [HR] = 4.11, 95% confidence interval [CI] 1.41-12.0, P = 0.01) after adjusting for potential covariates. On multivariate logistic regression analysis, GAR was strongly associated with an increased risk of 3 month poor function outcome. CONCLUSIONS: Stress hyperglycemia, quantified by a higher GAR, is associated with all-cause mortality and poor functional outcomes in patients with AIS who undergo MT. Furthermore, GAR may contribute to improving the predictive efficiency of all-cause mortality in patients with AIS after MT, especially short-term all-cause mortality.

[Circular RNA Cbl proto-oncogene B (circCBLB) inhibits proliferation, promotes apoptosis, and increases anti-inflammatory cytokine levels of fibroblast-like synoviocytes in rheumatoid arthritis].

Objective To explore the regulatory axis of circular RNA Cbl proto-oncogene B (circCBLB)/miR-486-5p on the proliferation, apoptosis, and inflammatory cytokines of fibroblast-like synoviocytes in rheumatoid arthritis (RA-FLS). Methods Human RA-FLS were stimulated with 100 µL of 10 ng/mL of tumor necrosis factor-alpha (TNF-α) to establish the model. The binding relationship of circCBLB/miR-486-5p was validated by a dual-luciferase reporter gene assay. pcDNA3.1/siRNA-circCBLB, negative control (pcDNA3.1-NC/si-NC), and miR-486-5p-mimics were created and transfected into RA-FLS, respectively. The experiment was divided into seven groups: control, TNF-α-treated RA-FLS, pcDNA3.1-circCBLB, pcDNA3.1-NC, si-circCBLB, si-NC, and pcDNA3.1-circCBLB combined with miR-486-5p-mimics. Cell viability was assessed by a CCK-8 assay; cell cycle and apoptosis by flow cytometry; colony formation ability by a colony formation assay; and the expression levels of circCBLB and miR-486-5p by real-time quantitative PCR. The levels of interleukin 4 (IL-4), IL-10, IL-6 and TNF-α were measured by ELISA. Results The dual-luciferase reporter gene assay showed that circCBLB bound to the 3' untranslated region (3'UTR) of miR-486-5p. Compared with the model group at the same time point, the cell viability of the overexpression group was lower, while that of the interference group was higher. Compared with the model group, the overexpression group had a higher apoptosis rate, a higher proportion in S and G2 phases, a lower colony formation rate, a lower miR-486-5p expression level, higher IL-4 and IL-10 levels, and lower IL-6 and TNF-α levels. The interference group had a lower apoptosis rate, a lower proportion in S and G2 phases, a higher colony formation rate, a higher miR-486-5p expression level, and a higher TNF-α level. The pcDNA3.1-circCBLB combined with miR-486-5p-mimics group reversed the effects of circCBLB on cell viability, apoptosis rate, cell cycle, colony formation ability, antiinflammatory cytokines, and proinflammatory cytokines. Conclusion circCBLB inhibits the viability of RA-FLS, increases apoptosis rate, prolongs the cell cycle, reduces colony formation ability, increases antiinflammatory cytokines, and decreases proinflammatory cytokines. In contrast, miR-486-5p has opposite regulatory effects on circCBLB and can partially reverse and offset the effects of circCBLB.

A novel pharmaceutical preparation of Tripterygium wilfordii Hook. f. regulates macrophage polarization to alleviate inflammation in rheumatoid arthritis.

OBJECTIVES: To validate the enhanced therapeutic effect of Tripterygium wilfordii Hook. f. (TWHF) in the treatment of rheumatoid arthritis (RA) by restoring homeostasis of M1/M2 macrophages. METHODS: This study, using random walk models and network pharmacology, examined the molecular targets and mechanism of TWHF in RA. Based on clinical observations and experiments in arthritis animal models, the effects of TWHF on macrophage polarization, related signal pathways, and targets were examined. Triptolide, a component of TWHF, was used to intervene arthritis rats. KEY FINDINGS: Network pharmacological analysis revealed the key RA target genes related to TWHF. TWHF showed a strong correlation with the improvement of inflammatory indicators. TWHF inhibited the factors secreted by M1 macrophages such as IL-1ß, IL-6, CXCL8, TNF-α, and VEGF-A, but promoted IL-10 from M2 macrophages. Quantitative liquid-phase chip assay showed that triptolide reduced the levels of TNF-α, CXCL2, and VEGF, while IL-4 and IL-10 were increased in arthritis model. Meanwhile, triptolide inhibited the NF-κB, PI3K/AKT, and p38 MAPK signaling pathways, which in turn improved the RA joint inflammation and fixed immune imbalance. CONCLUSIONS: Triptolide downregulate the expression of M1 macrophage-secreted factors that inhibit the overactivation of inflammatory signaling pathways.

Role of m6A modification and novel circ_0066715/ miR-486-5p/ ETS1 axis in rheumatoid arthritis macrophage polarization progression.

Rheumatoid arthritis (RA) is a systemic disease dominated by inflammatory synovitis. RA synovial macrophages tend undergo M1-type macrophage polarization. Then, polarized M1-type macrophages secrete abundant pro-inflammatory cytokines, causing joint and cartilage destruction. N6-methyladenosine (m6A) methylation modification, circular RNA (circRNA), microRNA (miRNA), messenger RNA (mRNA), etc. are involved in the inflammatory response of RA. We found that there is an imbalance of inflammatory polarization in RA, which is manifested by a sharp increase in inflammatory markers and a high inflammatory response. Here, we show that RA was closely associated with low expression of circ_0066715. The overexpression of circ_0066715 significantly increased the ETS1 levels in RA-FLS cells, decreased cytokine secretion by M1-type macrophages, elevated M2-type cytokines, and inhibited FLS proliferation. Interestingly, the overexpression of miR-486-5p significantly suppressed the attenuation of the cell function and the effect on M1 macrophage polarization caused by circ_0066715 positive expression. WTAP may be involved in the methylation process of ETS1 in RA. ETS1 m6A methylation levels were altered upon WTAP intervention. The overexpression or interference of circ_0066715 decreased or increased WTAP expression. Our findings provide a novel circRNA/miRNA/mRNA regulatory axis and m6A regulatory mechanism involved in the process of RA macrophage polarization, thereby providing a powerful diagnostic and therapeutic strategy for RA treatment.

Prenatal immune stress blunts microglia reactivity, impairing neurocircuitry.

Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function1,2. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood3,4. Several maternal environmental factors-such as an aberrant microbiome, immune activation and poor nutrition-can influence prenatal brain development5,6. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that, after maternal immune activation (MIA) in mice, microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was accompanied by changes in chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single-cell RNA-sequencing analysis revealed that MIA does not induce a distinct subpopulation but, rather, decreases the contribution to inflammatory microglia states. Prenatal replacement of microglia from MIA offspring with physiological infiltration of naive microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment affect the long-term microglia reactivity and proper striatal circuit development.

The association between stress hyperglycemia and unfavorable outcomes in patients with anterior circulation stroke after mechanical thrombectomy.

Background and purpose: Stress hyperglycemia is common in critical and severe diseases. However, few studies have examined the association between stress hyperglycemia and the functional outcomes of patients with anterior circulation stroke, after mechanical thrombectomy (MT), in different diabetes status. This study therefore aimed to determine the relationship between stress hyperglycemia and the risk of adverse neurological functional outcomes in anterior circulation stroke patients with and without diabetes after MT. Methods: Data of 408 patients with acute anterior circulation stroke treated with MT through the green-channel treatment system for emergency stroke at the First Affiliated Hospital of Jinan University between January 2016 and December 2020 were reviewed retrospectively. The stress hyperglycemia ratio (SHR) was calculated as fasting plasma glucose (mmol/L) divided by glycosylated hemoglobin (%). The patients were stratified into four groups by quartiles of SHR (Q1-Q4). The primary outcome was an excellent (nondisabled) functional outcome at 3 months after admission (modified Rankin Scale score of 0-1). The relationship between stress hyperglycemia and neurological outcome after stroke was assessed using multivariate logistic regression. Results: After adjusting for potential confounders, compared with patients in Q1, those in Q4 were less likely to have an excellent outcome at 3 months (odds ratio [OR], 0.32, 95% confidence interval [CI], 0.14-0.66, p = 0.003), a good outcome at 3 months (OR, 0.41, 95% CI, 0.20-0.84, p = 0.020), and major neurological improvement (OR, 0.38, 95% CI, 0.19-0.73, p = 0.004). Severe stress hyperglycemia increased risks of 3-months all-cause mortality (OR, 2.82, 95% CI, 1.09-8.29, p = 0.041) and ICH (OR, 2.54, 95% CI, 1.21-5.50, p = 0.015). Conclusion: Stress hyperglycemia was associated with a reduced rate of excellent neurological outcomes, and increased mortality and ICH risks in patients with anterior circulation stroke after MT regardless of diabetes status.

Responses of Low-Quality Soil Microbial Community Structure and Activities to Application of a Mixed Material of Humic Acid, Biochar, and Super Absorbent Polymer.

Low-quality soil for land reuse is a crucial problem in vegetation quality and especially to waste disposal sites in mining areas. It is necessary to find suitable materials to improve the soil quality and especially to increase soil microbial diversity and activity. In this study, pot experiments were conducted to investigate the effect of a mixed material of humic acid, super absorbent polymer and biochar on low-quality soil indexes and the microbial community response. The indexes included soil physicochemical properties and the corresponding plant growth. The results showed that the mixed material could improve chemical properties and physical structure of soil by increasing the bulk density, porosity, macro aggregate, and promote the mineralization of nutrient elements in soil. The best performance was achieved by adding 3 g·kg-1 super absorbent polymer, 3 g·kg-1 humic acid, and 10 g·kg-1 biochar to soil with plant total nitrogen, dry weight and height increased by 85.18%, 266.41% and 74.06%, respectively. Physicochemical properties caused changes in soil microbial diversity. Acidobacteria, Bacteroidetes, Chloroflexi, Cyanobacteria, Firmicutes, Nitrospirae, Planctomycetes, and Proteobacteria were significantly positively correlated with most of the physical, chemical and plant indicators. Actinobacteria and Armatimonadetes were significantly negatively correlated with most measurement factors. Therefore, this study can contribute to improving the understanding of low-quality soil and how it affects soil microbial functions and sustainability.

Monolayer graphene film on ZnO nanorod array for high-performance Schottky junction ultraviolet photodetectors.

A new Schottky junction ultraviolet photodetector (UVPD) is fabricated by coating a free-standing ZnO nanorod (ZnONR) array with a layer of transparent monolayer graphene (MLG) film. The single-crystalline [0001]-oriented ZnONR array has a length of about 8-11 µm, and a diameter of 100∼600 nm. Finite element method (FEM) simulation results show that this novel nanostructure array/MLG heterojunction can trap UV photons effectively within the ZnONRs. By studying the I-V characteristics in the temperature range of 80-300 K, the barrier heights of the MLG film/ZnONR array Schottky barrier are estimated at different temperatures. Interestingly, the heterojunction diode with typical rectifying characteristics exhibits a high sensitivity to UV light illumination and a quick response of millisecond rise time/fall times with excellent reproducibility, whereas it is weakly sensitive to visible light irradiation. It is also observed that this UV photodetector (PD) is capable of monitoring a fast switching light with a frequency as high as 2250 Hz. The generality of the above results suggest that this MLG film/ZnONR array Schottky junction UVPD will have potential application in future optoelectronic devices.

Construction of high-quality CdS:Ga nanoribbon/silicon heterojunctions and their nano-optoelectronic applications.

Silicon based optoelectronic integration is restricted by its poor optoelectronic properties arising from the indirect band structure. Here, by combining silicon with another promising optoelectronic material, the CdS nanoribbon (NR), devices with heterojunction structure were constructed. The CdS NRs were also doped with gallium to improve their n-type conductivity. A host of nano-optoelectronic devices, including light emitting diodes, photovoltaic devices, and photodetectors, were successfully constructed on the basis of the CdS:Ga NR/Si heterojunctions. They all exhibited excellent device performances as regards high stability, high efficiency, and fast response speed. It is expected that the CdS NR/Si heterojunctions will have great potential for future applications of Si based optoelectronic integration.

[Combination of acupuncture, cupping and medicine for treatment of fibromyalgia syndrome: a multi-central randomized controlled trial].

OBJECTIVE: To evaluate the clinical effect of combination of acupuncture, cupping and medicine for treatment of fibromyalgia syndrome. METHODS: By using multi-central randomized controlled method, 186 cases were randomly divided into an acupuncture combined with cupping and western medicine group (group A), an acupuncture combined with cupping group (group B) and a western medicine group (group C) and treated continuously for 4 weeks. The treatment of acupuncture combined with cupping was produced by acupuncture at five mental points and moving cupping on the Hechelu of the back, once evrey other day, thrice each week, and the western medicine therapy by oral administration of Amitriptyline, once each day. The scores of McGill Pain Questionnaire (MPQ), the amount of tenderness point and the time of producing effect were compared and the therapeutic effects were assessed with the Hamilton Depression Scale (HAMD). RESULTS: The cured and markedly effective rate was 65.0% (39/60) in the group A, which was superior to 15.9% (10/63) in the group B and 16.1% (9/56) in the group C (both P < 0.001). After treatment, the scores of MPQ and HAMD and the amount of tenderness point all decreased in the three groups, group A being significantly better than group B and group C, and the time of producing effect in the group A was more earlier than those in the group B and the group C. CONCLUSION: The therapeutic effect of combination of acupuncture, cupping and medicine on fibromyalgia syndrome is superior to that of the simple acupuncture combined with cupping or the simple medicine.

Association of hsp70-2 and hsp-hom gene polymorphisms with risk of acute high-altitude illness in a Chinese population.

High-altitude illness (HAI) is a potentially fatal condition involving genetic and environmental components. Accumulated experimental evidence suggests that heat shock proteins (Hsps), especially HSP70, can protect cells and organs against different types of damage. We investigated whether genetic variation in constitutive and inducible hsp70 genes could be associated with risk of HAI. The association between polymorphisms of the HSP70 family genes and risk of HAI was determined in 56 patients with HAI and in 100 matched controls by genotyping for the polymorphisms +190 G/C, +1267 A/G, 2437 G/C in the hsp70-1, hsp70-2, and hsp70-hom genes by using polymerase chain reaction-restriction fragment length polymorphism. The data showed that there was no statistically significant difference in the genotype and allele distributions of hsp70-1, in hsp70-2 allele and hsp70-2 A/A and A/B genotypes, and in allele distribution of hsp70-hom among patients with HAI and controls (chi2 test, P > 0.05). However, there was a significantly higher frequency of hsp70-2 B/B and hsp70-hom A/A and B/B genotypes and a significantly lower frequency of the hsp70-hom A/B genotype in the HAI patients compared with the controls (P < 0.05 for all). The risk associated with the hsp70-2 B/B and hsp70-hom A/A, A/B, and B/B genotypes were 4.017 (95% CI = 1.496-10.781; P = 0.004), 2.434 (95% CI = 1.184-5.003; P = 0.012), 0.299 (95% CI = 0.148-0.602, P = 0.001), and 5.880 (95% CI =1.145-30.196, P = 0.026), respectively. Our results suggest that individuals with hsp70-2 B/B and hsp70-hom A/B and B/B genotypes may be more susceptible to HAI, whereas those with hsp70-hom A/B genotype may be tolerant to HAI. Further studies in individuals of different age and sex are warranted to elucidate the underlying mechanisms of this association and the possible functions of different genotypes of hsp70-2 and hsp70-hom under hypoxic stress.

[Glutathione S-transferase M1, T1 genotypes and the risk of mountain sickness].

OBJECTIVE: To explore the relationship between genetic polymorphisms of glutathione S-transferase (GST) M1, T1 and susceptibility to mountain sickness. METHODS: Forty-three soldiers with acute mountain sickness and 80 healthy soldiers matching with sex/age and training under the same condition were divided into case group and control group. A multiple polymerase chain reaction method was used to detect GSTM1 and GSTT1 genes in genomic DNA isolated from peripheral blood cells from both cases and controls. RESULTS: The frequency of the GSTT1 positive genotype was significantly higher in cases (69.8%) than in controls (42.5%) (P = 0.004, OR = 3.12, 95% CI 1.42 approximately 6.86). The frequency of GSTM1 negative genotype was also higher in cases (72.1%) than in controls (52.5%) (P = 0.03, OR = 2.34, 95% CI 1.05 approximately 5.02). Persons with both GSTM1 and GSTT1 negative genotypes had 5-fold more risk than those with GSTT1 negative and GSTM1 positive genotypes in developing mountain sickness (OR = 5.04, 95% CI: 1.00 approximately 25.3). CONCLUSION: Genetic polymorphisms of glutathione S-transferase M1, T1 may be the risk factors in the development of mountain sickness.

[Relationship between heat stress protein 70 gene polymorphisms and the risk of acute mountain sickness].

OBJECTIVE: To investigate the relationship between heat stress proteins 70 (HSPs70) gene polymorphism and the risk of acute mountain sickness. METHODS: Fifty-six soldiers with acute mountain sickness and 173 soldiers without that were chosen as cases and controls. HSP70-1, HSP70-2 genotypes were analyzed by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: The HSP70-1 polymorphism was similar in two groups. The genotype frequency of HSP70-2 B/B in acute mountain sickness group (23.2%) was significantly higher than that in the control (6.9%, P < 0.05, OR = 4.02). CONCLUSION: There is a significantly increased association of HSP70-2 B/B genotype with the risk of acute mountain sickness. Individuals with HSP70-2 B/B genotype may have weaker adaptive ability than those without this genotype under altitude stress. The results contribute to provide scientific bases for finding these individuals in specified occupational people, ensuring their health and enhancing work efficiency.

[Difference in lymphocyte heat shock protein 71 (HSP71) expression in soldiers of armed police forces from different climatic zones].

OBJECTIVE: To analyze the difference between basal and heat-inducible levels of lymphocyte heat shock protein 71 (HSP71) expression in soldiers from Beijing, Zhengzhou and Guangzhou. METHODS: Flow cytometry and Comet assay were used to detect the level of HSP71 and DNA damage respectively. RESULTS: Comet assay showed that there was no significant DNA damage before and after heat stress at 41 degrees C for 1 h, and also no difference found among the 3 climatic zones(P > 0.05). HSP71 of all soldiers in the 3 zones elevated after stress (P < 0.05). The basal and heat-inducible levels of HSP71 in Beijing soldiers(845.87 +/- 135.60 and 1254. 47 +/- 239.05 mean fluorescence intensity respectively) were higher than those in Guangzhou soldiers(702.73 +/- 184.70 and 861.72 +/- 225.12 mean fluorescence intensity respectively) (P < 0.05). CONCLUSION: The differences of lymphocyte HSP71 expression before and after heat stress among the soldiers from Beijing, Zhengzhou and Guangzhou suggest that basal and heat-inducible levels of lymphocyte HSP71 expression may be considered as a valuable index to evaluate heat tolerance of soldiers in different climatic zones.