Interactions between circulating inflammatory factors and autism spectrum disorder: a bidirectional Mendelian randomization study in European population.

Background: Extensive observational studies have reported an association between inflammatory factors and autism spectrum disorder (ASD), but their causal relationships remain unclear. This study aims to offer deeper insight into causal relationships between circulating inflammatory factors and ASD. Methods: Two-sample bidirectional Mendelian randomization (MR) analysis method was used in this study. The genetic variation of 91 circulating inflammatory factors was obtained from the genome-wide association study (GWAS) database of European ancestry. The germline GWAS summary data for ASD were also obtained (18,381 ASD cases and 27,969 controls). Single nucleotide polymorphisms robustly associated with the 91 inflammatory factors were used as instrumental variables. The random-effects inverse-variance weighted method was used as the primary analysis, and the Bonferroni correction for multiple comparisons was applied. Sensitivity tests were carried out to assess the validity of the causal relationship. Results: The forward MR analysis results suggest that levels of sulfotransferase 1A1, natural killer cell receptor 2B4, T-cell surface glycoprotein CD5, Fms-related tyrosine kinase 3 ligand, and tumor necrosis factor-related apoptosis-inducing ligand are positively associated with the occurrence of ASD, while levels of interleukin-7, interleukin-2 receptor subunit beta, and interleukin-2 are inversely associated with the occurrence of ASD. In addition, matrix metalloproteinase-10, caspase 8, tumor necrosis factor-related activation-induced cytokine, and C-C motif chemokine 19 were considered downstream consequences of ASD. Conclusion: This MR study identified additional inflammatory factors in patients with ASD relative to previous studies, and raised a possibility of ASD-caused immune abnormalities. These identified inflammatory factors may be potential biomarkers of immunologic dysfunction in ASD.

Evidence that robot-assisted gait training modulates neuroplasticity after stroke: An fMRI pilot study based on graph theory analysis.

OBJECTIVES: To investigate alterations of whole-brain network after stroke and therapeutic mechanisms of robot-assisted gait training (RAGT). METHODS: 21 stroke patients and 20 healthy subjects were enrolled, with the stroke patients randomized to either control group (n = 11) or robot group (n = 10), and resting-state functional magnetic resonance imaging data were collected. The global network metrics were obtained using graph theory analysis and compared between stroke patients and healthy subjects, and the effect of the RAGT on the whole-brain networks was explored. RESULTS: Compared to healthy subjects, area under the curve (AUC) for small-worldness (σ), clustering coefficient (Cp), global efficiency (Eg) and mean local efficiency (Eloc) were significantly lower in stroke patients, whereas AUC for characteristic path length (Lp) were significantly higher. Compared with the control group, patients in robot group showed significant improvement in lower limb motor function, balance function and walking function after intervention, with a significant reduction in the AUC of Cp. Moreover, the improvement of walking function was positively correlated with the changes of AUC of σ and Eg, and negatively correlated with the changes of AUC of Cp. CONCLUSIONS: Small-worldness and network efficiency were significantly reduced after stroke, whereas RAGT decreased characteristic path length and promoted normalization of the whole-brain network, and this change was associated with improvement in walking function. Our findings reveal the mechanism by which RAGT regulates network reorganization and neuroplasticity after stroke.

Neurotrophin-4 promotes in vitro development and maturation of human secondary follicles yielding metaphase II oocytes and successful blastocyst formation.

STUDY QUESTION: Does a matrix-free culture system supplemented with neurotrophic factor 4 (NT4) improve human in vitro follicular development and meiotic maturation, ultimately resulting in fertilizable oocytes? SUMMARY ANSWER: NT4 supplementation of in vitro culture significantly enhances the growth, steroid hormone production, and maturity potential of human secondary follicles derived from fresh ovarian medulla (from post- and pre-pubertal patients), thereby yielding fertilizable oocytes. WHAT IS KNOWN ALREADY: Reconstituting folliculogenesis in vitro is of paramount importance in the realms of fertility preservation, reproductive biology research, and reproductive toxicity assessments. However, the efficiency of in vitro culture systems remains suboptimal, as the attainment of fertilizable oocytes from in vitro growth (IVG) of human follicles remains unachieved, with the data being particularly scant regarding follicles from prepubertal girls. We have previously found that mouse oocytes from secondary follicles derived from IVG are deficient in neuroendocrine regulation. NT4 and its corresponding receptor have been identified in human follicles. Significantly, the addition of NT4 during the IVG process markedly enhances both follicle growth and oocyte maturation rates in mice. STUDY DESIGN SIZE DURATION: Fresh medulla tissue obtained during tissue preparation for ovarian tissue cryopreservation (OTC) were collected from 10 patients aged from 6 to 21 years old, all of whom had undergone unilateral oophorectomy as a means of fertility preservation. Isolated secondary follicles were individually cultured in vitro with or without NT4 in a matrix-free system. PARTICIPANTS/MATERIALS SETTING METHODS: Secondary follicles, extracted via enzymatic digestion and mechanical disruption from each patient, were randomly allocated to either a control group or an NT4-supplemented group (100 ng/ml), followed by individual culture on an ultra-low attachment plate. Follicle growth and viability were assessed by microscopy. Levels of anti-Müllerian hormone (AMH), estradiol, and progesterone in the medium were quantified. An oocyte-specific marker was identified using confocal fluorescence microscopy following DEAD box polypeptide 4 (DDX4) staining. The competence of individual oocytes for maturation and fertilization were assessed after IVM and ICSI with donated sperm samples. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, isolated follicles from both groups survived up to 6 weeks with increasing diameters over the duration (P < 0.05), reaching terminal diameters of almost 1 mm with confirmed steroidogenesis and expression of oocyte marker (DDX4), and producing morphologically normal MII oocytes. When compared with the control group, the NT4 group had a similar initial follicular diameter (206 ± 61.3 vs 184 ± 93.4 µm) but exhibited a significant increase in follicular diameter from the ninth day of culture onwards (P < 0.05). From Week 3, estradiol and progesterone production were significantly increased in the NT4 group, while no significant difference was observed in AMH production between groups. The proportion of 'fast-growth' follicles in the NT4 group was significantly higher than that in the control group (13/23 vs 6/24, P < 0.05). An increased efficiency of MII oocyte maturation per live follicle in the NT4 group was also observed (control group vs NT4 group, 4/24 vs 10/23, P < 0.05). It is noteworthy that an MII oocyte obtained from the control group exhibited abnormal fertilization after ICSI. In contrast, an MII oocyte acquired from the NT4 group progressed to the blastocyst stage and showed potential for transfer. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The cohort examined in this study was all patients diagnosed with beta-thalassemia major. Whether this culture system is effective for patients with other diseases remains unknown. Since the chosen dose of NT4 was established based on dose finding in mice, the optimal dose for use in a human IVG system needs further confirmation. The oocytes and embryos procured from this study have not been quantified for ploidy status or epigenetic signatures. WIDER IMPLICATIONS OF THE FINDINGS: Fresh medulla tissue obtained during tissue preparation for OTC may serve as a precious source of fertilizable oocytes for female fertility preservation, even for pre-pubertal girls, without the threat of tumour reintroduction. After further characterization and optimization of the system, this culture system holds the potential to provide a powerful future research tool, for the comprehensive exploration of human follicular development mechanisms and for conducting reproductive toxicity evaluations. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Key R&D Program of China (grant number 2022YFC2703000) and National Natural Science Foundation of China (grant numbers 82271651 and 81871214). The medium used in human follicle in vitro culture in this study has been applied for a national invention patent in China (No. 202211330660.7). The inventors of the patent, in order, are: Y.G., C.F., and X.L.

Predictors of Cognitive Functions After Stroke Assessed Using the Wechsler Adult Intelligence Scale: A Retrospective Study.

Background: The mechanism(s) of cognitive impairment remains complex, making it difficult to confirm the factors influencing poststroke cognitive impairment (PSCI). Objective: This study quantitatively investigated the degree of influence and interactions of clinical indicators of PSCI. Methods: Information from 270 patients with PSCI and their Wechsler Adult Intelligence Scale (WAIS-RC) scores, totaling 18 indicators, were retrospectively collected. Correlations between the indicators and WAIS scores were calculated. Multiple linear regression model(MLR), genetic algorithm modified Back-Propagation neural network(GA-BP), logistic regression model (LR), XGBoost model (XGB), and structural equation model were used to analyze the degree of influence of factors on the WAIS and their mediating effects. Results: Seven indicators were significantly correlated with the WAIS scores: education, lesion side, aphasia, frontal lobe, temporal lobe, diffuse lesions, and disease course. The MLR showed significant effect of education, lesion side, aphasia, diffuse lesions, and frontal lobe on the WAIS. The GA-BP included five factors: education, aphasia, frontal lobe, temporal lobe, and diffuse lesions. LR predicted that the lesion side contributed more to mild cognitive impairment, while education, lesion side, aphasia, and course of the disease contributed more to severe cognitive impairment. XGB showed that education, side of the lesion, aphasia, and diffuse lesions contributed the most to PSCI. Aphasia plays a significant mediating role in patients with severe PSCI. Conclusions: Education, lesion side, aphasia, frontal lobe, and diffuse lesions significantly affected PSCI. Aphasia is a mediating variable between clinical information and the WAIS in patients with severe PSCI.