Electroacupuncture modulates abnormal brain connectivity after ischemia reperfusion injury in rats: A graph theory-based approach.

BACKGROUND: Electroacupuncture (EA) has been shown to facilitate brain plasticity-related functional recovery following ischemic stroke. The functional magnetic resonance imaging technique can be used to determine the range and mode of brain activation. After stroke, EA has been shown to alter brain connectivity, whereas EA's effect on brain network topology properties remains unclear. An evaluation of EA's effects on global and nodal topological properties in rats with ischemia reperfusion was conducted in this study. METHODS AND RESULTS: There were three groups of adult male Sprague-Dawley rats: sham-operated group (sham group), middle cerebral artery occlusion/reperfusion (MCAO/R) group, and MCAO/R plus EA (MCAO/R + EA) group. The differences in global and nodal topological properties, including shortest path length, global efficiency, local efficiency, small-worldness index, betweenness centrality (BC), and degree centrality (DC) were estimated. Graphical network analyses revealed that, as compared with the sham group, the MCAO/R group demonstrated a decrease in BC value in the right ventral hippocampus and increased BC in the right substantia nigra, accompanied by increased DC in the left nucleus accumbens shell (AcbSh). The BC was increased in the right hippocampus ventral and decreased in the right substantia nigra after EA intervention, and MCAO/R + EA resulted in a decreased DC in left AcbSh compared to MCAO/R. CONCLUSION: The results of this study provide a potential basis for EA to promote cognitive and motor function recovery after ischemic stroke.

Design, synthesis, and biological evaluation of novel benzimidazole derivatives as anti-cervical cancer agents through PI3K/Akt/mTOR pathway and tubulin inhibition.

Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for cervical cancer treatment. In this study, we designed and synthesized a series of benzimidazole derivatives and evaluated their anti-cervical cancer activity. Compound 4r exhibited strong antiproliferative activity in different cervical cancer cell lines HeLa, SiHa and Ca Ski, and relative lower cytotoxicity to normal hepatic and renal cell lines LO2 and HEK-293t (IC50 values were at 21.08 µM and 23.96 µM respectively). Its IC50 value was at 3.38 µM to the SiHa cells. Further mechanistic studies revealed that 4r induced apoptosis, arrested cell cycle in G2/M phase, suppressed PI3K/Akt/mTOR pathway and inhibit the polymerization of tubulin. Molecular docking study suggested that 4r formed key H-bonds action with PI3Kα (PDB ID:8EXU) and tubulin (PDB ID:1SA0). Zebrafish acute toxicity experiments showed that high concentrations of 4r did not cause death or malformation of zebrafish embryos. All these results demonstrated that 4r would be a promising lead candidate for further development of novel PI3K and tubulin dual inhibitors in cervical cancer treatment.

Tetracycline inhibits tick host reproduction by modulating bacterial microbiota, gene expression and metabolism levels.

BACKGROUND: Ticks are disease vectors that are a matter of worldwide concern. Antibiotic treatments have been used to explore the interactions between ticks and their symbiotic microorganisms. In addition to altering the host microbial community, antibiotics can have toxic effects on the host. RESULTS: In the tick Haemaphysalis longicornis, engorged females showed reproductive disruption after microinjection of tetracycline. Multi-omics approaches were implemented to unravel the mechanisms of tick reproductive inhibition in this study. There were no significant changes in bacterial density in the whole ticks on Day (D)2 or D4 after tetracycline treatment, whereas the bacterial microbial community was significantly altered, especially on D4. The relative abundances of the bacteria Staphylococcus, Bacillus and Pseudomonas decreased after tetracycline treatment, whereas the relative abundances of Coxiella and Rhodococcus increased. Ovarian transcriptional analysis revealed a cumulative effect of tetracycline treatment, as there was a significant increase in the number of differentially expressed genes with treatment time and a higher number of downregulated genes. The tick physiological pathways including lysosome, extracellular matrix (ECM)-receptor interaction, biosynthesis of ubiquinone and other terpenoids-quinones, insect hormone biosynthesis, and focal adhesion were significantly inhibited after 4 days of tetracycline treatment. Metabolite levels were altered after tetracycline treatment and the differences increased with treatment time. The differential metabolites were involved in a variety of physiological pathways; the downregulated metabolites were significantly enriched in the nicotinate and nicotinamide metabolism, galactose metabolism, and ether lipid metabolism pathways. CONCLUSIONS: These findings indicate that tetracycline inhibits tick reproduction through the regulation of tick bacterial communities, gene expression and metabolic levels. The results may provide new strategies for tick control. © 2023 Society of Chemical Industry.

Mechanism of the toxic effects of tetracycline on blood meal digestion in Haemaphysalis longicornis.

The extensive utilization of antibiotics in the field of animal husbandry gives rise to various concerns pertaining to the environment and human health. Here, we demonstrate that the administration of tetracycline impedes blood meal digestion in the tick Haemaphysalis longicornis. Tissue sectioning, 16S rRNA high-throughput sequencing, and transcriptome sequencing of the midgut were employed to elucidate the mechanism underlying tetracycline toxicity. The treatment group consisted of engorged female ticks that were subjected to tetracycline microinjections (75 µg per tick), whereas the control group received sterile water injections. On days 2 and 4 following the injections, the tick body weight changes were assessed and the midguts were dissected and processed. Change in tick body weight in tetracycline-treated group was less than in the control group. In tetracycline-treated ticks, midgut epithelial cells were loosely connected and blood meal digestion was impaired compared to the control group. There was no significant change in midgut bacterial diversity after tetracycline treatment. On day 2 following treatment, the relative abundance of Escherichia-Shigella was significantly decreased, whereas the relative abundance of Allorhizobium was significantly increased compared to the control group. On day 4 following treatment, the relative abundance of Escherichia-Shigella, Allorhizobium, Ochrobactrum, and Acidibacter decreased significantly, whereas the relative abundance of Paraburkholderia and Pelomonas increased significantly. Tetracycline treatment also affected midgut gene expression, producing a cumulative effect wherein the differentially expressed genes (DEGs) were mostly down-regulated. KEGG enrichment pathway analysis revealed that on day 2 the up-regulated DEGs were significantly enriched in 21 pathways, including apoptosis and phagosome. Comparatively, the down-regulated DEGs were significantly enriched in 26 pathways, including N-glycan biosynthesis, lysosome, and autophagy. In contrast, on day 4 the up-regulated DEGs were significantly enriched in 10 pathways including aminoacyl-tRNA biosynthesis, ribosome biogenesis, RNA transport, and DNA replication, whereas the down-regulated differential genes were significantly enriched in 11 pathways including lysosome, peroxisome, N-glycan biosynthesis, and fatty acid synthesis. This indicates that tetracycline injection inhibited blood meal digestion by affecting midgut digestive cells, gut flora diversity, and gene expression. These findings could contribute to tick control by inhibiting blood meal digestion.

[Role of Flow Cytometry in the Diagnosis of Chronic Myeloid Leukemia].

OBJECTIVE: To analyze the immunological phenotype of chronic myeloid leukemia (CML), and explore its characteristics and significance. METHODS: The immunophenotypes of 40 CML children and 40 controls were analyzed by multicolor flow cytometry. CD45/SSC, as the basic gate, was used to delineate neutrophils. Then, the distribution of cluster differentiation (CD) molecules on the surface of granulocytes was analyzed in three ranges (≥1%, ≥5%, and ≥20%), and the expression rates of CD molecules (≥1% included in the statistical analysis) and the mean fluorescence intensity (MFI) were compared between the two groups. RESULTS: The proportion of granulocytes in the CML group was (82.1±6.4)%, which was significantly higher than (57.8±11.8)% in the control group (P <0.001). The expression rates of CD15/CD11b/CD33/CD13 in CML and control groups were high, and both distributed in the range of ≥20%. The differentiation trajectory of CD33/CD13 was normal and there were no significant differences in the expression rate and MFI between the two groups. However, both the expression rate of CD11b and CD15 MFI in the CML group were significantly lower than those in the control group (P <0.001). There were no significant differences in the expression rate and MFI of CD10 between the two groups, and the expression levels of CD10 between the two groups were consistent in different distributions. In the CML group, there was a large number of cases with abnormal high expression of CD56, 52.5% of the cases had a CD56 expression rate of ≥5%, and 42.5% had a CD56 expression rate of ≥20%, while the control group did not express CD56 (<1%). The expression distribution of CD117 was different between the two groups. In the range of expression rate ≥5%, there were 35.0% cases in the CML group, while only 2.5% in the control group. The expression rate of CD117 in the CML group was higher than that in the control group (P <0.001), though there was no significant difference in MFI. CONCLUSION: The immunophenotyping of CML is characterized by increased proportion of mature neutrophils, decreased CD15 MFI, decreased proportion of CD11b and abnormal high expression of CD56 and CD117. Flow cytometric analysis of immunophenotype can effectively distinguish normal granulocytes from chronic granulocytes, and help in the diagnosis of CML.

Focal ischemic stroke modifies microglia-derived exosomal miRNAs: potential role of mir-212-5p in neuronal protection and functional recovery.

BACKGROUND: Ischemic stroke is a severe type of stroke with high disability and mortality rates. In recent years, microglial exosome-derived miRNAs have been shown to be promising candidates for the treatment of ischemic brain injury and exert neuroprotective effects. Mechanisms underlying miRNA dysregulation in ischemic stroke are still being explored. Here, we aimed to verify whether miRNAs derived from exosomes exert effects on functional recovery. METHODS: MiR-212-5p agomir was employed to upregulate miR-212-5p expression in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) as well as an oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. Western blot analysis, qRT-PCR and immunofluorescence staining and other methods were applied to explore the underlying mechanisms of action of miR-212-5p. RESULTS: The results of our study found that intervention with miR-212-5p agomir effectively decreased infarct volume and restored motor function in MCAO/R rats. Mechanistically, miR-212-5p agomir significantly reduced the expression of PlexinA2 (PLXNA2). Additionally, the results obtained in vitro were similar to those achieved in vivo. CONCLUSION: In conclusion, the present study indicated that PLXNA2 may be a target gene of miR-212-5p, and miR-212-5p has great potential as a target for the treatment and diagnosis of ischemic stroke.

Clinical characteristics of severe influenza virus-associated pneumonia complicated with bacterial infection in children: a retrospective analysis.

BACKGROUND: We aimed to investigate the clinical characteristics of severe influenza virus-associated pneumonia complicated with bacterial infection in children. METHODS: We retrospectively analysed data concerning 64 paediatric patients with severe influenza virus-associated pneumonia who had been treated at our hospital. The patients were divided into observation (44 patients) and control (20 patients) groups, based on the presence or absence of concomitant bacterial infection, and clinical data were compared between the groups. RESULTS: The mean age in the observation group was 2.71 ± 1.44 years, 42 (95.45%) were aged ≤ 5 years, and 18 (40.9%) had underlying diseases. The mean age in the control group was 4.05 ± 2.21 years, 13 (65%) were aged ≤ 5 years, and 3 (15%) had underlying diseases. There was a statistically significant difference in patient age and the proportion of patients with underlying diseases (P < 0.05). The observation group had higher duration of fever values, a higher number of patients with duration of fever ≥ 7 days, a higher incidence of gasping, and a higher incidence of seizures/consciousness disturbance, and the differences were statistically significant (P < 0.05). Secondary bacterial infections in the observation group were mainly due to gram-negative bacteria, with Haemophilus influenzae and Moraxella catarrhalis being the most common pathogens. The observation group had a higher proportion of patients treated in the paediatric intensive care unit and a longer hospital stay, and the differences were statistically significant (P < 0.05). CONCLUSION: Severe influenza virus-associated pneumonia complicated with bacterial infection was more common in children aged ≤ 5 years. Younger patients with underlying diseases were more susceptible to bacterial infection (mainly due to gram-negative bacteria). The timely administration of neuraminidase inhibitors and antibiotics against susceptible bacteria is likely to help improve cure rates.

Use of 3D-printing cerebral aneurysm model assisting microcatheter shaping in neurovascular intervention technique training.

BACKGROUND: Microcatheter shaping plays a vital role in coil embolization of cerebral aneurysms, while the complicated method and insufficient training opportunities make it difficult for junior neurovascular clinicians to master this technique. In this program, we constructed a novel training method and assessment system for microcatheter shaping in coil embolization of cerebral aneurysms with 3D technique, and evaluated its efficacy for microcatheter shaping training in junior neurovascular clinicians. METHODS: Patient-specific models for cerebral aneurysms in different locations and with different morphologies were selected by experienced senior neurovascular clinicians. The solid polylactic acid model and the soft hollow crystal silicone model of intracranial aneurysms were then made separately for shaping reference and assessment in the training course. Twelve residents without prior experience of microcatheter shaping and 25 neurovascular clinicians who have in vivo experience of microcatheter shaping on 3-5 occasions were selected for this training program and randomly divided into the traditional training group and the experimental training group. Four senior neurovascular clinicians assisted and guided the trainees in two groups and evaluated the time and accuracy of microcatheter shaping. RESULTS: Eighteen trainees were assigned to the traditional training group, among which 4 had prior experience in microcatheter shaping. The other 19 were assigned to the experimental training group, including 8 with prior experience. No statistical difference in the distribution of experienced students between the two groups was noted(P = 0.295). After the training session, the shaping time was found shorter in the experimental training group than that in the traditional training group (40.3.5 ± 16.2 s vs. 54.2 ± 16.4 s, P = 0.014), while the shaping score was found higher in the experimental training group than that in the traditional training group (4.4 ± 0.5 vs. 2.6 ± 1.2, P < 0.001). Specifically, for the trainees without prior experience, the experimental training group also showed less time consumption and higher score (Time: 52.7 ± 7.7 vs. 61.5 ± 9.5, P = 0.02; Score 4.1 ± 0.5 vs. 2.3 ± 1.1, P < 0.01). Meanwhile, for the trainees with prior experience, the advantage was noted in shaping score (4.7 ± 0.3 vs. 3.9 ± 0.6, P < 0.01) but not in time consumption (23.3 ± 4.4 vs. 28.5 ± 3.9, P = 0.07). CONCLUSION: This training program is quite effective at teaching junior neurovascular physicians the essential surgical abilities required for coiling cerebral aneurysms.

Cerebral 18 F-fluorodeoxyglucose metabolism alteration of reward- and motivation-related regions in groups of different BMI classifications.

OBJECTIVE: This study explored the relationship between BMI and regional cerebral glucose metabolism and explicitly detected regions with significant differences in cerebral metabolism using positron emission tomography (PET)/magnetic resonance imaging in the resting state. METHODS: Corresponding PET images acquired from 220 participants were sorted into four groups according to Asian BMI standards: underweight, normal weight, overweight, and obesity. Pearson correlation coefficient analysis was performed to assess the association between BMI and standard uptake value. The regional cerebral glucose metabolism was measured in the fasted state. The PET images were analyzed using statistical parameter maps. One-way ANOVA was used to explore differences in the standard uptake value as an indicator of regional cerebral glucose metabolism. RESULTS: This study found that lower cerebral glucose metabolism in reward- and motivation-related regions was accompanied by more severe obesity and that regional cerebral glucose metabolism activities were negatively correlated with BMI. In addition, more severe obesity was accompanied by a larger range of areas with significant differences independent of current dietary status. CONCLUSIONS: These findings suggest that the reward and motivation circuits may be a factor regulating energy balance and influencing the degree of obesity.

Alteration of brain functional networks induced by electroacupuncture stimulation in rats with ischemia-reperfusion: An independent component analysis.

Motor dysfunction is the major sequela of ischemic stroke. Motor recovery after stroke has been shown to be associated with remodeling of large-scale brain networks, both functionally and structurally. Electroacupuncture (EA) is a traditional Chinese medicine application that has frequently been recommended as an alternative therapy for ischemic stroke and is reportedly effective for alleviating motor symptoms in patients. In the present study, the effect of EA on the alterations of functional resting state networks (RSNs) was explored after middle cerebral artery occlusion/reperfusion (MCAO/R) injury using resting-state functional MRI. Rats were randomly assigned to three groups, including the sham group, MCAO/R group and MCAO/R+EA group. The ladder rung walking test was conducted prior to and after modeling to assess behavioral changes. RSNs were identified based on the independent component analysis (ICA) performed on the fMRI data from groups. EA treatment effectively reduced the occurrence of contralateral forelimb foot faults. Furthermore, our results suggested the disrupted function of the whole-brain network following ischemic stroke and the modulatory effect of acupuncture. The sensorimotor network (SMN), interoceptive network (IN), default mode network (DMN) and salience network (SN) were related to the therapeutic effect of EA on stroke recovery. Collectively, our findings confirmed the effect of EA on motor function recovery after cerebral ischemia reperfusion and shed light on the assessment of EA intervention-induced effects on brain networks. This study provides neuroimaging evidence to explain the therapeutic effects of EA in ischemic stroke and will lay the groundwork for further studies.

Growth dynamics and tissue localization of a Coxiella-like endosymbiont in the tick Haemaphysalis longicornis.

A Coxiella-like endosymbiont (Coxiella-LE hereinafter) stably infects and influences Haemaphysalis longicornis development, indicating a mutualistic relationship of Coxiella-LE and ticks. To further elucidate the patterns of growth dynamics and tissue localization of Coxiella-LE in H. longicornis, 16S rRNA high-throughput sequencing, quantitative PCR (qPCR), and fluorescence in situ hybridization (FISH) were used in this study. The density of Coxiella-LE varied among different tick life stages, and fed female ticks had the highest density, followed by unfed female and unfed larval ticks. In the four organs that were dissected from fed female ticks, the ovary carried the highest density of Coxiella-LE, which was significantly different from salivary glands, midgut and Malpighian tubules. The high abundance of Coxiella-LE in fed female ticks and in the ovaries of fed female ticks in the bacterial microbiota analyses further confirmed that Coxiella-LE rapidly proliferates in the ovary after blood feeding. The ovaries continued to develop after engorgement and oviposition began on day 5, with a significant decrease in the density of Coxiella-LE in the ovaries occurring on day 7. FISH results indicated that Coxiella-LE is mainly colonized in the cytoplasm of the oocyte and proliferates with oogenesis. Coxiella-LE was expelled from the body with the mature oocyte, ensuring its vertical transmission. In the Malpighian tubules at different days after engorgement, the white flocculent materials were increasing, and the density of Coxiella-LE raised significantly on day 7. Unlike the localization pattern in the ovary, Coxiella-LE was initially distributed in a mass and continually increased during the development of Malpighian tubules until it filled the Malpighian tubules. These findings provide new insights on the growth dynamics and tissue localization of Coxiella-LE in ticks and are useful for further investigation on the interactions of symbiont and ticks .

Brain Function and Upper Limb Deficit in Stroke With Motor Execution and Imagery: A Cross-Sectional Functional Magnetic Resonance Imaging Study.

Background: Motor imagery training might be helpful in stroke rehabilitation. This study explored if a specific modulation of movement-related regions is related to motor imagery (MI) ability. Methods: Twenty-three patients with subcortical stroke and 21 age-matched controls were recruited. They were subjectively screened using the Kinesthetic and Visual Imagery Questionnaire (KVIQ). They then underwent functional magnetic resonance imaging (fMRI) while performing three repetitions of different motor tasks (motor execution and MI). Two separate runs were acquired [motor execution tasks (ME and rest) and motor imagery (MI and rest)] in a block design. For the different tasks, analyses of cerebral activation and the correlation of motor/imagery task-related activity and KVIQ scores were performed. Results: During unaffected hand (UH) active grasp movement, we observed decreased activations in the contralateral precentral gyrus (PreCG), contralateral postcentral gyrus (PoCG) [p < 0.05, family wise error (FWE) corrected] and a positive correlation with the ability of FMA-UE (PreCG: r = 0.46, p = 0.028; PoCG: r = 0.44, p = 0.040). During active grasp of the affected hand (AH), decreased activation in the contralateral PoCG was observed (p < 0.05, FWE corrected). MI of the UH induced significant activations of the contralateral superior frontal gyrus, opercular region of the inferior frontal gyrus, and ipsilateral ACC and deactivation in the ipsilateral supplementary motor area (p < 0.05, AlphaSim correction). Ipsilateral anterior cingulate cortex (ACC) activity negatively correlated with MI ability (r = =-0.49, p = 0.022). Moreover, we found significant activation of the contralesional middle frontal gyrus (MFG) during MI of the AH. Conclusion: Our results proved the dominant effects of MI dysfunction that exist in stroke during the processing of motor execution. In the motor execution task, the enhancement of the contralateral PreCG and PoCG contributed to reversing the motor dysfunction, while in the MI task, inhibition of the contralateral ACC can increase the impaired KVIQ ability. The bimodal balance recovery model can explain our results well. Recognizing neural mechanisms is critical to helping us formulate precise strategies when intervening with electrical or magnetic stimulation.

Bacterial microbiota analysis demonstrates that ticks can acquire bacteria from habitat and host blood meal.

Ticks have a diversity of habitats and host blood meals. Whether and how factors such as tick developmental stages, habitats and host blood meals affect tick bacterial microbiota is poorly elucidated. In the present study, we investigated the bacterial microbiotas of the hard tick Haemaphysalis longicornis, their blood meals and habitats using 16S rRNA gene high-throughput sequencing. The bacterial richness and diversity in ticks varied depending on the tick developmental stage and feeding status. Results showed that fed ticks present a higher bacterial richness suggesting that ticks may acquire bacteria from blood meals. The significant overlap of the bacteria of fed ticks and the host blood also supports this possibility. Another possibility is that blood meals can stimulate the proliferation of certain bacteria. However, most shared bacteria cannot transmit throughout the tick life cycle, as they were not present in tick eggs. The most shared bacteria between ticks and habitats are members of the genera Staphylococcus, Pseudomonas, Enterobacter, Acinetobacter and Stenotrophomonas, suggesting that these environmental bacteria cannot be completely washed away and can be acquired by ticks. The predominant proportion of Coxiella in fed females further demonstrates that this genus is involved in H. longicornis physiology, such as feeding activity and nutritional provision. These findings further reveal that the bacterial composition of ticks is influenced by a variety of factors and will help in subsequent studies of the function of these bacteria.

Cerebral Metabolic Analysis of Patients With Colorectal Cancer and Chronic Enteritis: Inquiry Into Gut-Brain Crosstalk.

Gut-brain crosstalk has been demonstrated previously. However, brain metabolic patterns of colorectal cancer and chronic enteritis remain unclear. A better understanding of gut-brain crosstalk from a radiological perspective is necessary. We conducted a retrospective study in which we acquired 18F-fluorodeoxyglucose positron emission tomography in 45 colorectal cancer cases, 45 age- and sex-matched chronic enteritis patients, and 45 age- and sex-matched healthy controls. We calculated a scaled sub-profile pattern based on principal component analysis and metabolic connectivity to explore the brain metabolic model and analyzed correlations between various brain regions and cancer to identify potential neuroimaging markers for non-pharmaceutical therapies. We found a characteristic cerebral metabolic pattern in colorectal cancer patients, which mainly involved visceral sensation and both affective and cognitive psychological processes. The metabolic patterns of patients with colorectal cancer and chronic enteritis were similar but not identical. The metabolic connectivity of the postcentral gyrus and paracentral lobule was found to be significantly different between the controls and patients with colorectal cancer (p < 0.05, false discovery rate correction). The maximal standard uptake value of the cancer focus in colorectal cancer patients was negatively correlated with the dorsolateral superior frontal gyrus (p < 0.05). Patients with colorectal cancer may show abnormal glucose cerebral metabolism characterized by "point-line-surface." This preliminary study revealed the cerebral metabolic characteristics and neurobiological mechanisms of colorectal cancer and chronic enteritis (ChiCTR2000041020; registered December 16, 2020).

Autophagy-based unconventional secretion of HMGB1 in glioblastoma promotes chemosensitivity to temozolomide through macrophage M1-like polarization.

BACKGROUND: Glioblastoma (GB) is the most common and highly malignant brain tumor characterized by aggressive growth and resistance to alkylating chemotherapy. Autophagy induction is one of the hallmark effects of anti-GB therapies with temozolomide (TMZ). However, the non-classical form of autophagy, autophagy-based unconventional secretion, also called secretory autophagy and its role in regulating the sensitivity of GB to TMZ remains unclear. There is an urgent need to illuminate the mechanism and to develop novel therapeutic targets for GB. METHODS: Cancer genome databases and paired-GB patient samples with or without TMZ treatment were used to assess the relationship between HMGB1 mRNA levels and overall patient survival. The relationship between HMGB1 protein level and TMZ sensitivity was measured by immunohistochemistry, ELISA, Western blot and qRT-PCR. GB cells were engineered to express a chimeric autophagic flux reporter protein consisting of mCherry, GFP and LC3B. The role of secretory autophagy in tumor microenvironment (TME) was analyzed by intracranial implantation of GL261 cells. Coimmunoprecipitation (Co-IP) and Western blotting were performed to test the RAGE-NFκB-NLRP3 inflammasome pathway. RESULTS: The exocytosis of HMGB1 induced by TMZ in GB is dependent on the secretory autophagy. HMGB1 contributed to M1-like polarization of tumor associated macrophages (TAMs) and enhanced the sensitivity of GB cells to TMZ. Mechanistically, RAGE acted as a receptor for HMGB1 in TAMs and through RAGE-NFκB-NLRP3 inflammasome pathway, HMGB1 enhanced M1-like polarization of TAMs. Clinically, the elevated level of HMGB1 in sera may serve as a beneficial therapeutic-predictor for GB patients under TMZ treatment. CONCLUSIONS: We demonstrated that enhanced secretory autophagy in GB facilitates M1-like polarization of TAMs to enhance TMZ sensitivity of GB cells. HMGB1 acts as a key regulator in the crosstalk between GB cells and tumor-suppressive M1-like TAMs in GB microenvironment and may be considered as an adjuvant for the chemotherapeutic agent TMZ.

Alteration of the Individual Metabolic Network of the Brain Based on Jensen-Shannon Divergence Similarity Estimation in Elderly Patients With Type 2 Diabetes Mellitus.

The aim of this study was to investigate the interactive effect between aging and type 2 diabetes mellitus (T2DM) on brain glucose metabolism, individual metabolic connectivity, and network properties. Using a 2 × 2 factorial design, 83 patients with T2DM (40 elderly and 43 middle-aged) and 69 sex-matched healthy control subjects (HCs) (34 elderly and 35 middle-aged) underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance scanning. Jensen-Shannon divergence was applied to construct individual metabolic connectivity and networks. The topological properties of the networks were quantified using graph theoretical analysis. The general linear model was used to mainly estimate the interaction effect between aging and T2DM on glucose metabolism, metabolic connectivity, and network. There was an interaction effect between aging and T2DM on glucose metabolism, metabolic connectivity, and regional metabolic network properties (all P < 0.05). The post hoc analyses showed that compared with elderly HCs and middle-aged patients with T2DM, elderly patients with T2DM had decreased glucose metabolism, increased metabolic connectivity, and regional metabolic network properties in cognition-related brain regions (all P < 0.05). Age and fasting plasma glucose had negative correlations with glucose metabolism and positive correlations with metabolic connectivity. Elderly patients with T2DM had glucose hypometabolism, strengthened functional integration, and increased efficiency of information communication mainly located in cognition-related brain regions. Metabolic connectivity pattern changes might be compensatory changes for glucose hypometabolism.

Microstructural changes of white matter assessed with diffusional kurtosis imaging in extremely preterm infants with severe intraventricular hemorrhage.

Objective: Intraventricular hemorrhage (IVH) is a serious neurological complication in premature infants. This study aimed to investigate the white matter impairments and neurodevelopmental outcomes of severe IVH in extremely preterm infants with gestation age less than 28 weeks. Methods: We retrospectively evaluated the extremely preterm infants between 2017 and 2020. Neurodevelopmental outcomes were evaluated with the Bayley Scales of Infant and Toddler Development-III at 2 years of corrected age. Diffusional kurtosis imaging (DKI) was employed to evaluate the microstructural changes in white matter tracts. Mean kurtosis (MK) and fractional anisotropy (FA) values of DKI were measured in the brain regions including posterior limbs of the internal capsule (PLIC) and the corpus callosum at term equivalent age. Results: Of 32 extremely preterm infants with severe IVH during the follow-up period, 18 cases were identified as neurodevelopmental impairments. The delay rates of motor and language were 58.4% and 52.7%. The cases with neurodevelopmental impairments had lower MK and FA values in both bilateral PLIC and the corpus callosum. The analysis of multivariable regression models predicting motor and language outcomes at 2 years of corrected age, showed that the decreases of MK values in both PLIC and the corpus callosum at the term equivalent age contributed to a significantly increased risk of neurodevelopmental impairments (all p < 0.05). During follow-up period, obvious loss of nerve fiber bundles was observed with DKI tractography. Conclusion: Motor and language abilities at age 2 years were associated with MK values of DKI at the term equivalent age in both PLIC and the corpus callosum of extremely preterm infants with severe IVH. The evaluation of white matter microstructural changes with MK values might provide feasible indicators of neurodevelopmental outcomes of extremely preterm infants with severe intraventricular hemorrhage.

Electroacupuncture treatment improves motor function and neurological outcomes after cerebral ischemia/reperfusion injury.

Electroacupuncture (EA) has been widely used for functional restoration after stroke. However, its role in post-stroke rehabilitation and the associated regulatory mechanisms remain poorly understood. In this study, we applied EA to the Zusanli (ST36) and Quchi (LI11) acupoints in rats with middle cerebral artery occlusion and reperfusion. We found that EA effectively increased the expression of brain-derived neurotrophic factor and its receptor tyrosine kinase B, synapsin-1, postsynaptic dense protein 95, and microtubule-associated protein 2 in the ischemic penumbra of rats with middle cerebral artery occlusion and reperfusion. Moreover, EA greatly reduced the expression of myelin-related inhibitors Nogo-A and NgR in the ischemic penumbra. Tyrosine kinase B inhibitor ANA-12 weakened the therapeutic effects of EA. These findings suggest that EA can improve neurological function after middle cerebral artery occlusion and reperfusion, possibly through regulating the activity of the brain-derived neurotrophic factor/tyrosine kinase B signal pathway. All procedures and experiments were approved by the Animal Research Committee of Shanghai University of Traditional Chinese Medicine, China (approval No. PZSHUTCM200110002) on January 10, 2020.

Effective connectivity decreases in specific brain networks with postparalysis facial synkinesis: a dynamic causal modeling study.

Currently, the treatments for postparalysis facial synkinesis are still inadequate. However, neuroimaging mechanistic studies are very limited and blurred. Instead of mapping activation regions, we were devoted to characterizing the organizational features of brain regions to develop new targets for therapeutic intervention. Eighteen patients with unilateral facial synkinesis and 19 healthy controls were enrolled. They were instructed to perform task functional magnetic resonance imaging (eye blinking and lip pursing) examinations and resting-state scans. Then, we characterized group differences in task-state fMRI to identify three foci, including the contralateral precentral gyrus (PreCG), supramarginal gyrus (SMG), and superior parietal gyrus (SPG). Next, we employed a novel approach (using dynamic causal modeling) to identify directed connectivity differences between groups in different modes. Significant patterns in multiple regions in terms of regionally specific actions following synkinetic movements were demonstrated, although the resting state was not significant. The couplings from the SMG to the PreCG (p = 0.03) was significant in the task of left blinking, whereas the coupling from the SMG to the SPG (p = 0.04) was significant in the task of left smiling. We speculated that facial synkinesis affects disruption among the brain networks, and specific couplings that are modulated simultaneously can compensate for motor deficits. Therefore, behavioral or brain stimulation technique treatment could be applied to alter reorganization within specific couplings in the rehabilitation of facial function.

Brain Structural Changes in Carpal Tunnel Syndrome Patients: From the Perspectives of Structural Connectivity and Structural Covariance Network.

BACKGROUND: Carpal tunnel syndrome (CTS) is a common peripheral entrapment neuropathy. However, CTS-related changes of brain structural covariance and structural covariance networks (SCNs) patterns have not been clearly studied. OBJECTIVE: To explore CTS-related brain changes from perspectives of structural connectivity and SCNs. METHODS: Brain structural magnetic resonance images were acquired from 27 CTS patients and 19 healthy controls (HCs). Structural covariance and SCNs were constructed based on gray matter volume. The global network properties including clustering coefficient (Cp), characteristic path length (Lp), small-worldness index, global efficiency (Eglob), and local efficiency (Eloc) and regional network properties including degree, betweenness centrality (BC), and Eloc of a given node were calculated with graph theoretical analysis. RESULTS: Compared with HCs, the strength of structural connectivity between the dorsal anterior insula and medial prefrontal thalamus decreased (P < .001) in CTS patients. There was no intergroup difference of area under the curve for Cp, Lp¸ Eglob, and Eloc (all P > .05). The real-world SCN of CTS patients showed a small-world topology ranging from 2% to 32%. CTS patients showed lower nodal degrees of the dorsal anterior insula and medial prefrontal thalamus, and higher Eloc of a given node and BC in the lateral occipital cortex (P < .001) and the dorsolateral middle temporal gyrus (P < .001) than HCs, respectively. CONCLUSION: CTS had a profound impact on brain structures from perspectives of structural connectivity and SCNs.