Magnetic resonance imaging R2* sequences can better detect microstructural cartilage changes than T2 mapping in cynomolgus monkeys with limited knee kinematics: preliminary imaging findings.

BACKGROUND: The difference between MRI (Magnetic resonance imaging)-R2* and T2 mapping sequences regarding their superiority in the detection of microstructural cartilage changes in knees with limited ROM (range of motion) was unknown. METHODS: Twenty male cynomolgus monkeys (mean age: 10.65 ± 0.97 years) underwent knee ROM evaluations and were divided into three groups: Group A (n = 10), with similar left and right knee ROM; Group B (n = 5), with left knee ROM superior to right; and Group C (n = 5), with left knee ROM inferior to right. Twenty-eight ROIs (regions of interest) in the cartilage of the lateral (L) and medial (M) femoral trochlea (FT), anterior (A)/central (C)/posterior (P) femoral condyle (FC) and tibial plateau (TP) of both knees were identified in each monkey. The corresponding ROI values in R2* and T2 mapping sequences were recorded for analysis. One-way ANOVA, Chi-square tests and Pearson's correlation analysis were used for statistical analyses. RESULTS: Among the total 1120 ROIs, significant differences in R2* values among the three groups existed in two ROIs: cartilage of the right MPTP (F = 5.216, P = 0.017) and left MAFC (F = 4.919, P = 0.021). However, the T2 mapping values of all ROIs were similar among the three groups. Microstructural cartilage changes occurred more frequently in the medial (40 ROIs) than in the lateral (0 ROIs) knee compartment (χ2 = 43.077, P < 0.001). The Group B cartilage R2* value of the right MPTP increased with the difference in bilateral knee ROM (r = 0.913, P = 0.030). CONCLUSIONS: In knees with limited ROM, MRI-R2* sequence is superior to T2 mapping in the detection of microstructural cartilage changes, which the medial knee compartment was more susceptible to. Cartilage R2* values tend to increase with the amount of knee ROM loss.

Fe3O4 Nanozymes Improve Neuroblast Differentiation and Blood-Brain Barrier Integrity of the Hippocampal Dentate Gyrus in D-Galactose-Induced Aged Mice.

Aging is a process associated with blood-brain barrier (BBB) damage and the reduction in neurogenesis, and is the greatest known risk factor for neurodegenerative disorders. However, the effects of Fe3O4 nanozymes on neurogenesis have rarely been studied. This study examined the effects of Fe3O4 nanozymes on neuronal differentiation in the dentate gyrus (DG) and BBB integrity of D-galactose-induced aged mice. Long-term treatment with Fe3O4 nanozymes (10 µg/mL diluted in ddH2O daily) markedly increased the doublecortin (DCX) immunoreactivity and decreased BBB injury induced by D-galactose treatment. In addition, the decreases in the levels of antioxidant proteins including superoxide dismutase (SOD) and catalase as well as autophagy-related proteins such as Becin-1, LC3II/I, and Atg7 induced by D-galactose treatment were significantly ameliorated by Fe3O4 nanozymes in the DG of the mouse hippocampus. Furthermore, Fe3O4 nanozyme treatment showed an inhibitory effect against apoptosis in the hippocampus. In conclusion, Fe3O4 nanozymes can relieve neuroblast damage and promote neuroblast differentiation in the hippocampal DG by regulating oxidative stress, apoptosis, and autophagy.

Noggin, an inhibitor of bone morphogenetic protein signaling, antagonizes TGF-ß1 in a mouse model of osteoarthritis.

Osteoarthritis (OA) is the most common joint disease worldwide; however, disease-modifying treatments are lacking because of the complicated pathological mechanisms. As a breakthrough, aberrant activation of transforming growth factor-ß 1 (TGF-ß1)in subchondral bone has been confirmed as an essential pathomechanism for OA progression, and has become a potential therapeutic target. In addition to R&D on neutralizing antibodies, small-molecule antagonists and chemical medicines, native antagonists of TGF-ß1 could be exploited as another promising approach. Noggin (NOG) is an antagonist of bone morphogenetic proteins (BMPs) and was reported to effectively attenuate OA by protecting cartilage and preventing pathological subchondral bone remodeling. However, the underlying mechanisms have not been fully clarified. We first detected the distribution of NOG in knee joints of an OA mouse model, which showed upregulation at early stage of OA but downregulation later in the subchondral bone and no significant change in the articular cartilage. Furthermore, the interaction between NOG and TGF-ß1 was verified, which in turn suppressed the downstream SMAD2/3 activity of TGF-ß1. Moreover, the proliferation and chondrogenesis of mesenchymal stem cells (MSCs) were not significantly influenced by NOG. Taken together, the results showed that NOG antagonized TGF-ß1 but did not repress MSC proliferation and chondrogenesis; thus, it seems promising for OA treatment.

Expression of Long Non-coding RNA RGD1566344 in the Brain Cortex of Male Mice After Focal Cerebral Ischemia-Reperfusion and the Neuroprotective Effect of a Non-coding RNA RGD1566344 Inhibitor.

Ischemic stroke (IS) remains a major cause of disability and death. The changes in long non-coding RNA (lncRNA) RGD1566344 expression in the mouse cerebral cortex, including the infarct and penumbra regions after IS, are not clear. Less is known about the impact and underlying mechanisms of RGD1566344 in IS. In this study, we found that RGD1566344 levels were elevated in the ischemic infarct and penumbra regions 12 h after middle cerebral artery occlusion/reperfusion (MCAO/R) in male mice and in PC12 cells with oxygen glucose deprivation/reperfusion (OGD/R). The inhibition of RGD1566344 by small interference RNA (siRNA) significantly alleviated apoptosis in OGD/R PC12 cells. In cell transfection, quantitative real-time PCR, and Western blot experiments, we demonstrated the possible interaction of non-POU domain-containing octamer-binding protein (NONO) with RGD1566344. The NONO level in OGD/R PC12 cells was obviously increased after inhibiting the RGD1566344 treatment; subsequently the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway was activated. This demonstrated the effect of the RGD1566344-NONO-AKT axis on neural protection after IS. These results revealed a new molecular mechanism of lncRNA RGD1566344 inhibitors through targeting NONO/AKT/mTOR signaling to protect against ischemic neuronal injury, providing strong evidence for the development of promising therapeutic strategies against IS.

TRIM33 is essential for osteoblast proliferation and differentiation via BMP pathway.

Tripartite motif containing 33 (TRIM33) functions both as a positive and negative regulator of the TGF-ß/BMP pathway in tumors; however, its effect and mechanism during osteoblast proliferation and differentiation, which involves the TGF-ß/BMP pathway is not defined. In this study, we used mouse C3H10T1/2 mesenchymal stem cell line and MC3T3-E1 preosteoblasts to investigate the role of TRIM33 during this process. The results demonstrated that the expression of TRIM33 increased during the differentiation. Moreover, the overexpression or knockdown of TRIM33 resulted in both an augmentation or decrease in osteoblast differentiation, which were measured by the expression of alkaline phosphatase (ALP) at the mRNA level, both Runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) at the protein level, and the formation of mineral modules. To further demonstrate the mechanism of TRIM33 in this process, we found that TRIM33 could positively mediate the BMP pathway by forming TRIM33-Smad1/5 complex. This interaction between TRIM33 and Smad1/5 triggered the phosphorylation of Smad1/5. In addition, the essential role of TRIM33 in osteoblast proliferation was determined in this study by CellCounting Kit (CCK) -8 and cell cycle assays. In summary, we establish the function of TRIM33 as a positive regulator of osteoblast differentiation in BMP pathway, which mediates its effect through its interaction with and activation of Smad1/5. In addition, the results clearly demonstrate that TRIM33 is necessary for osteoblast proliferation by regulating cell cycle. These results suggest that TRIM33 can be a positive target of osteoblast proliferation and differentiation through BMP pathway.

Biomechanical evaluation of monosegmental pedicle instrumentation in a calf spine model and the role of fractured vertebrae in screw stability.

BACKGROUND: Monsegmental pedicle instrumentation (MSPI) has been used to treat thoracolumbar fractures. However, there are few reports about the biomechanical characteristics of MSPI compared with traditional short-segment pedicle instrumentation (SSPI) in management of unstable thoracolumbar fractures, and the influence of vertebral fracture on screw stability is still unclear. METHODS: This study was to compare the immediate stability between MSPI and SSPI in management of unstable L1 fracture, and to evaluate the role of fractured vertebrae in screw stability. Two studies were performed: in the first study, sixteen fresh calf spines (T11-L3) were divided into two groups, in which unstable fractures at L1 were produced and then instrumented with MSPI or SSPI respectively. The range of motion (ROM) and lax zone (LZ) of specimens were evaluated with pure moment of 6 Nm loaded. The second study measured and compared the pullout strength of screws inserted in to 16 intact and fractured vertebrae of calf spines (L1-3) respectively. The correlation of pullout strength with load sharing classification (LSC) of fractured vertebrae was analyzed. RESULTS: No significant difference in the ROM and LZ of the destabilized segments after fixation between MSPI and SSPI, except in axial rotation of ROM (P < 0.05). After fatigue cyclic loading, the MSPI showed a significant increase of ROM during lateral bending and axial rotation (P < 0.05); however, there were no significant differences in the LZ during all loading models between groups (P > 0.05). The mean pullout strength of pedicle screws in fractured vertebrae decreased by 13.7%, compared with that of intact vertebrae (P > 0.05), and had a low correlation with LSC of the fractured vertebrae (r = 0.293, P > 0.05). CONCLUSIONS: MSPI can provide effective immediate stability for management of unstable thoracolumbar fractures; however, it has less fatigue resistance during lateral bending and axial rotation compared with SSPI. LSC score of fractured vertebrae is not a major influence on the pullout strength of screws.

Induction of chondrogenic differentiation of mouse embryonic mesenchymal stem cells through an in vitro pellet model.

This study employed transforming growth factor beta 3 (TGF-ß3) induction of the C3H10T1/2 mesenchymal stem cell (MSC) line to construct an in vitro chondrogenic differentiation model for MSCs. A C3H10T1/2 MSC cell line was cultured, amplified, and the seventh generation of cells was centrifuged to construct pellets, which were divided into a non-induced group and an induced group (treated with TGF-ß3, vitamin C, dexamethasone, and ITS). Specimens were taken after 7, 14, 21, and 28 days under non-induced and induced culture to compare these two groups by Alcian Blue staining, collagen type II immunohistochemical staining, and transmission election microscopy (TEM) on days 21 and 42. Cell pellets in the non-induced group were smaller than those in the induced group on days 7, 14, 21, and 28 with the pellet morphology of the induced group being more regular and nearly spherical. Alcian blue staining in the induced group was consistently stronger than that in non-induced group across all time points, and type II collagen immunohistochemical IOD values were significantly higher in the induced group over the non-induced group across all time points. On days 21 and 42, TEM revealed that the induced group displayed greater karyokinesis and a higher euchromatin ratio compared to the non-induced group. This specially constructed pellet model treated with TGF-ß3-containing chondrogenic medium can effectively promote chondrogenic differentiation of C3H10T1/2 MSC cells in vitro. This in vitro pellet model should be of value in providing a preliminary cell model reference for further studies of the mechanism of chondroblast differentiation of stem cells.

Cervical cage without plating in management of type II / II A Hangman's fracture combined with intervertebral disc injury.

BACKGROUND: Surgical intervention is increasingly performed as the primary treatment of unstable Hangman's fracture. Some authors have advocated using anterior C2/3 discectomy with interbody fusion and plating to treat unstable Hangman's fracture combined with intervertebral disc injury; however, there are few reports on unstable Hangman's fracture treated by anterior interbody fusion with the cervical cage (PEEK material) solely. METHODS: This study was to assess the efficacy of the cervical cage in management of unstable Hangman's fracture combined with intervertebral disc injury. A cohort of 15 patients with unstable Hangman's fractures fulfilling the inclusion criteria were prospectively submitted to surgical treatment of anterior C2/3 discectomy and interbody fusion using the cervical cage without plating. According to the Levine and Edwards classification, there were 5 type II, and 10 type IIA cases. The clinical outcome (the visual analog scale and the clinical post-traumatic neck score), radiological findings (angulation, translation, and disc height), and bone healing were assessed at 3, 6, 12, and 24 months. RESULTS: All the patients were followed up successfully. There were no intra- or postoperative complications observed. Solid fusion was achieved in all cases by 6 months after surgery. The local kyphotic angle was corrected significantly with the mean preoperative 12.31 ± 2.96 degrees, initial postoperative -1.98 ± 1.62 degrees and the latest follow-up -1.72 ± 1.60 degrees respectively (P < 0.05).The translation was also corrected significantly with the mean preoperative 3.20 ± 1.16 mm, initial postoperative 0.97 ± 0.36 mm, and the latest follow-up 1.05 ± 0.34 mm respectively (P < 0.05). The mean visual analog scale and the clinical post-traumatic neck score improved significantly following surgery (P < 0.05). CONCLUSIONS: This case series demonstrates that anterior C2/3 discectomy and interbody fusion with the cervical cage solely is effective and reliable in management of type II / IIA Hangman's fracture with C2/3 disc injury when properly indicated.

Comparison of artificial cervical arthroplasty versus anterior cervical discectomy and fusion for one-level cervical degenerative disc disease: a meta-analysis of randomized controlled trials.

PURPOSE: The aim of the study was to evaluate whether there is a superior clinical effect of artificial cervical arthroplasty compared with anterior cervical discectomy and fusion (ACDF) for the treatment of one-level cervical degenerative disc disease (CDDD). METHODS: A comprehensive literature search of multiple databases, including PubMed, ScienceDirect, Scopus, Embase, Cochrane Central Register of Controlled Trials, was conducted to identify studies that met the inclusion criteria. Methodological quality was assessed and relevant data were extracted, and if appropriate, meta-analysis was performed. RESULTS: Thirteen randomized controlled trials were identified. At 24 months post-operatively, total disc replacement (TDR) was demonstrated to be more beneficial for patients compared with ACDF for the following outcomes: neurological success [odds ratio (OR) 1.92; 95% confidence interval (CI) 1.47-2.49; p < 0.00001], range of motion [mean differences (MD), 6.67; 95% CI 4.82-8.53; p < 0.00001], secondary surgical procedures (OR 0.50; 95% CI 0.37-0.68; p < 0.00001), and visual analogue scale neck pain scores (MD -5.99; 95% CI -10.54 to -1.45; p = 0.001) and visual analogue scale arm pain scores (MD -3.23; 95% CI -6.48 to 0.02; p = 0.004). Other outcomes, including length of the hospital stay (MD -0.03; 95% CI -0.18 to 0.12; p = 0.68), blood loss (MD 6.92 mL; 95% CI -3.09 to 16.92 mL; p = 0.18), Neck Disability Index scores (MD -1.00; 95% CI -5.28 to 3.28; p = 0.65) and rate of adverse events [risk ratio (RR), 0.93; 95% CI 0.76-1.15; p = 0.52] demonstrated no differences between the 2 groups. Although the TDR group had a significantly longer operation time than the ACDF group, it was not considered clinically important. CONCLUSIONS: For patients with one-level CDDD, TDR was found to be more superior than ACDF in terms of neurological success, secondary surgical procedures, visual analogue scale pain scores and range of motion at 24 months post-operatively. Therefore, cervical arthroplasty is a safe and effective surgical procedure for treating one-level CDDD. We suggest adopting TDR on a large scale; with failure of TDR, ACDF would be performed.

In vivo experimental intervertebral disc degeneration induced by bleomycin in the rhesus monkey.

BACKGROUND: Recently, biological therapies for early intervention of degenerative disc disease have been introduced and developed; however, a functional animal model that mimics slowly progressive disc degeneration of humans does not exist. The objective of this study was to establish a slowly progressive and reproducible intervertebral disc (IVD) degeneration model. METHODS: The subchondral bone adjacent to the lumbar IVDs (L3/4 and L5/6) of ten rhesus monkeys was randomly injected with 4 ml bleomycin solution (1.5 mg/ml), or 4 ml phosphate buffer saline (PBS) per segment as control, respectively. The degenerative process was investigated by using radiography and T1ρ MR imaging at 1, 3, 6, 9, 12 and 15 months postoperatively. Histological scoring, Sulfated Glycosaminoglycans (GAGs) analysis and real-time PCR were performed at 15 months. The correlation between histological score, GAGs and T1ρ values were also analyzed. RESULTS: The results showed that the mean T1ρ values of nucleus pulposus (NP) and annulus fibrosus (AF) in the bleomycin group significantly decreased after 3 and 6 months respectively, followed by slowly decrease until at 15 months. At 15 months, the histological scores was significantly higher, and the GAGs of NP was significantly lower in the bleomycin group, compared with the control group (P<0.05). The results of real-time PCR revealed a significant increase in matrix metalloprotease (MMP)-3, A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5, tumor necrosis factor α, interleukin-1ß, interleukin-6 expressions, transforming growth factor (TGF-ß1) and marked reduction in aggrecan, type II collagen, von willebrand factor (vWF) expressions at the mRNA levels in the bleomycin group. Spearman correlation analysis showed a strong positive correlation between GAGs and T1ρ values of NP (r =0.740, P<0.01), and a significant inverse correlation between histological score and T1ρ values of NP and AF (r=-0.761, r=-0.729, respectively, P<0.01). CONCLUSIONS: Injection of bleomycin into the subchondral bone adjacent to the lumbar IVDs of rhesus monkeys can results in mild, slowly progressive disc degeneration, which mimics the onset of human disc degeneration. T1ρ MR imaging is an effective and noninvasive technique for assessment of early stage disc degeneration.

Patients with episodic migraine without aura have an increased rate of delayed discounting.

OBJECTIVE: This study aimed to explore decision-making impulsivity and its neural mechanisms in patients with episodic migraine without aura (EMoA). BACKGROUND: Previous evidence indicates increased impulsivity and altered reward processing in patients with chronic migraine and medication overuse; however, whether the same holds true for those with EMoA is unclear. METHODS: Patients newly diagnosed with EMoA (n = 51) and healthy controls (HC, n = 45) were recruited. All participants completed delay discounting task, cognitive assessments, a questionnaire for headache profile, and resting-state function magnetic resonance imaging scans. Resting-state functional connectivity (RSFC) between the regions of interest and the entire brain was explored. RESULTS: Patients with EMoA showed a steeper subjective discount rate than HCs (F = 4.74, p = .032), which was positively related to a history of migraines (r = .742, p < .001). RSFC among the ventral striatum (vSTR), ventromedial prefrontal cortex, and occipital cortex was lower in patients with EMoA than in control groups, which was correlated with history (r' = .294, p = .036) and subjective discount rate (r' = .380, p = .006). Additionally, discounting rates and RSFC between the vSTR and occipital regions were significantly abnormal in the triptan group than the non-triptan group. Mediating effect analysis indicated a significant mediating effect in the change in RSFC between the vSTR and occipital status, history of triptan use, and subjective discount rate. CONCLUSION: This study further elucidated that an increase in delayed discounting rate exists in patients with EMoA and is related to the abnormality of the value processing network.

Reduced production of Ethyl Carbamate in wine by regulating the accumulation of arginine in Saccharomyces cerevisiae.

Ethyl carbamate (EC), a multisite carcinogenic compound, is naturally produced from urea and ethanol in alcoholic beverages. In order to reduce the content of EC in wine, the accumulation of arginine in Saccharomyces cerevisiae was regulated by genetic modifying genes involved in arginine transport and synthesis pathways to reduce the production of urea. Knockout of genes encoding arginine permease (Can1p) and amino acid permease (Gap1p) on the cell membrane as well as argininosuccinate synthase (Arg1) respectively resulted in a maximum reduction of 66.88% (9.40 µg/L) in EC, while overexpressing the gene encoding amino acid transporter (Vba2) reduced EC by 52.94% (24.13 µg/L). Simultaneously overexpressing Vba2 and deleting Arg1 showed the lowest EC production with a decrease of 68% (7.72 µg/L). The yield of total higher alcohols of the mutants all decreased compared with that of the original strain. Comprehensive consideration of flavor compound contents and sensory evaluation results indicated that mutant YG21 obtained by deleting two allele coding Gap1p performed best in must fermentation of Cabernet Sauvignon with the EC content low to 9.40 µg/L and the contents of total higher alcohols and esters of 245.61 mg/L and 41.71 mg/L respectively. This study has provided an effective strategy for reducing the EC in wine.

Identification of coagulation diagnostic biomarkers related to the severity of spinal cord injury.

BACKGROUND: Blood always shows coagulation changes after spinal cord injury (SCI), and identifying these blood changes may be helpful for diagnosis and treatment of SCI. Nevertheless, studies to date on blood coagulation changes after SCI in humans are not comprehensive. Therefore, this study aims to identify blood coagulation diagnostic biomarkers and immune changes related to SCI and its severity levels. METHODS: Human blood sequencing datasets were obtained from public databases. Differentially expressed coagulation-related genes were analyzed (DECRGs). Enrichment analysis and assessment of immune changes were conducted. Weighted gene co-expression network analysis, least absolute shrinkage and selection operator logistic regression were used to identify biomarkers. Validation for these biomarkers was performed. The correlation between biomarkers and immune cells was evaluated. Transcription factors, miRNA, lncRNA, and drugs that can regulate biomarkers were analyzed. RESULTS: DECRGs associated with SCI and its different grades were identified, showing enrichment in altered coagulation and immune-related signaling pathways. ADAM9, CD55, and STAT4 were identified as coagulation diagnostic biomarkers for SCI. IRF4 and PABPC4 were identified as coagulation diagnostic biomarkers for American Spinal Injury Association Impairment Scale (AIS) A grade of SCI. GP9 was designated as a diagnostic biomarker for AIS D grade of SCI. Immune changes in blood of SCI and its different grades were observed. Correlation between diagnostic biomarkers and immune cells were identified. Transcription factors, miRNA, lncRNA, and drugs that can regulate diagnostic biomarker expression were discovered. CONCLUSION: Therefore, detecting the expression of these putative diagnostic biomarkers and related immune changes may be helpful for predicting the severity of SCI. Uncovering potential regulatory mechanisms for biomarkers may be beneficial for further research.

Abnormal EEG microstates in Alzheimer's disease: predictors of ß-amyloid deposition degree and disease classification.

Electroencephalography (EEG) microstates are used to study cognitive processes and brain disease-related changes. However, dysfunctional patterns of microstate dynamics in Alzheimer's disease (AD) remain uncertain. To investigate microstate changes in AD using EEG and assess their association with cognitive function and pathological changes in cerebrospinal fluid (CSF). We enrolled 56 patients with AD and 38 age- and sex-matched healthy controls (HC). All participants underwent various neuropsychological assessments and resting-state EEG recordings. Patients with AD also underwent CSF examinations to assess biomarkers related to the disease. Stepwise regression was used to analyze the relationship between changes in microstate patterns and CSF biomarkers. Receiver operating characteristics analysis was used to assess the potential of these microstate patterns as diagnostic predictors for AD. Compared with HC, patients with AD exhibited longer durations of microstates C and D, along with a decreased occurrence of microstate B. These microstate pattern changes were associated with Stroop Color Word Test and Activities of Daily Living scale scores (all P < 0.05). Mean duration, occurrences of microstate B, and mean occurrence were correlated with CSF Aß 1-42 levels, while duration of microstate C was correlated with CSF Aß 1-40 levels in AD (all P < 0.05). EEG microstates are used to predict AD classification with moderate accuracy. Changes in EEG microstate patterns in patients with AD correlate with cognition and disease severity, relate to Aß deposition, and may be useful predictors for disease classification.

A Study on the Effect of Executive Control Network Functional Connection on the Therapeutic Efficacy of Repetitive Transcranial Magnetic Stimulation in Alzheimer's Disease.

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by brain network dysfunction. Few studies have investigated whether the functional connections between executive control networks (ECN) and other brain regions can predict the therapeutic effect of repetitive transcranial magnetic stimulation (rTMS). Objective: The purpose of this study is to examine the relationship between the functional connectivity (FC) within ECN networks and the efficacy of rTMS. Methods: We recruited AD patients for rTMS treatment. We established an ECN using baseline period fMRI data and conducted an analysis of the ECN's FC throughout the brain. Concurrently, the support vector regression (SVR) method was employed to project post-rTMS cognitive scores, utilizing the connectional attributes of the ECN as predictive markers. Results: The average age of the patients was 66.86±8.44 years, with 8 males and 13 females. Significant improvement on most cognitive measures. We use ECN connectivity and brain region functions in baseline patients as features for SVR model training and fitting. The SVR model could demonstrate significant predictability for changes in Montreal Cognitive Assessment scores among AD patients after rTMS treatment. The brain regions that contributed most to the prediction of the model (the top 10% of weights) were located in the medial temporal lobe, middle temporal gyrus, frontal lobe, parietal lobe and occipital lobe. Conclusions: The stronger the antagonism between ECN and parieto-occipital lobe function, the better the prediction of cognitive improvement; the stronger the synergy between ECN and fronto-temporal lobe function, the better the prediction of cognitive improvement.

A causal examination of the correlation between hormonal and reproductive factors and low back pain.

Background: The relationship between hormonal fluctuations in the reproductive system and the occurrence of low back pain (LBP) has been widely observed. However, the causal impact of specific variables that may be indicative of hormonal and reproductive factors, such as age at menopause (ANM), age at menarche (AAM), length of menstrual cycle (LMC), age at first birth (AFB), age at last live birth (ALB) and age first had sexual intercourse (AFS) on low back pain remains unclear. Methods: This study employed Bidirectional Mendelian randomization (MR) using publicly available summary statistics from Genome Wide Association Studies (GWAS) and FinnGen Consortium to investigate the causal links between hormonal and reproductive factors on LBP. Various MR methodologies, including inverse-variance weighted (IVW), MR-Egger regression, and weighted median, were utilized. Sensitivity analysis was conducted to ensure the robustness and validity of the findings. Subsequently, Multivariate Mendelian randomization (MVMR) was employed to assess the direct causal impact of reproductive and hormone factors on the risk of LBP. Results: After implementing the Bonferroni correction and conducting rigorous quality control, the results from MR indicated a noteworthy association between a decreased risk of LBP and AAM (OR=0.784, 95% CI: 0.689-0.891; p=3.53E-04), AFB (OR=0.558, 95% CI: 0.436-0.715; p=8.97E-06), ALB (OR=0.396, 95% CI: 0.226-0.692; p=0.002), and AFS (OR=0.602, 95% CI: 0.518-0.700; p=3.47E-10). Moreover, in the reverse MR analysis, we observed no significant causal effects of LBP on ANM, AAM, LMC and AFS. MVMR analysis demonstrated the continued significance of the causal effect of AFB on LBP after adjusting for BMI. Conclusion: Our study explored the causal relationship between ANM, AAM, LMC, AFB, AFS, ALB and the prevalence of LBP. We found that early menarche, early age at first birth, early age at last live birth and early age first had sexual intercourse may decrease the risk of LBP. These insights enhance our understanding of LBP risk factors, offering valuable guidance for screening, prevention, and treatment strategies for at-risk women.

Brain functional specialization and cooperation in Alzheimer's disease.

BACKGROUND: Cerebral specialization and interhemispheric cooperation are two vital features of the human brain. Their dysfunction may be associated with disease progression in patients with Alzheimer's disease (AD), which is featured as progressive cognitive degeneration and asymmetric neuropathology. OBJECTIVE: This study aimed to examine and define two inherent properties of hemispheric function in patients with AD by utilizing resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: Sixty-four clinically diagnosed AD patients and 52 age- and sex-matched cognitively normal subjects were recruited and underwent MRI and clinical evaluation. We calculated and compared brain specialization (autonomy index, AI) and interhemispheric cooperation (connectivity between functionally homotopic voxels, CFH). RESULTS: In comparison to healthy controls, patients with AD exhibited enhanced AI in the left middle occipital gyrus. This increase in specialization can be attributed to reduced functional connectivity in the contralateral region, such as the right temporal lobe. The CFH of the bilateral precuneus and prefrontal areas was significantly decreased in AD patients compared to controls. Imaging-cognitive correlation analysis indicated that the CFH of the right prefrontal cortex was marginally positively related to the Montreal Cognitive Assessment score in patients and the Auditory Verbal Learning Test score. Moreover, taking abnormal AI and CFH values as features, support vector machine-based classification achieved good accuracy, sensitivity, specificity, and area under the curve by leave-one-out cross-validation. CONCLUSION: This study suggests that individuals with AD have abnormal cerebral specialization and interhemispheric cooperation. This provides new insights for further elucidation of the pathological mechanisms of AD.

Repetitive strikes loading organ culture model to investigate the biological and biomechanical responses of the intervertebral disc.

Background: Disc degeneration is associated with repetitive violent injuries. This study aims to explore the impact of repetitive strikes loading on the biology and biomechanics of intervertebral discs (IVDs) using an organ culture model. Methods: IVDs from the bovine tail were isolated and cultured in a bioreactor, with exposure to various loading conditions. The control group was subjected to physiological loading, while the model group was exposed to either one strike loading (compression at 38% of IVD height) or repetitive one strike loading (compression at 38% of IVD height). Disc height and dynamic compressive stiffness were measured after overnight swelling and loading. Furthermore, histological morphology, cell viability, and gene expression were analyzed on Day 32. Glycosaminoglycan (GAG) and nitric oxide (NO) release in conditioned medium were also analyzed. Results: The repetitive one strike group exhibited early disc degeneration, characterized by decreased dynamic compression stiffness, the presence of annulus fibrosus clefts, and degradation of the extracellular matrix. Additionally, this group demonstrated significantly higher levels of cell death (p < 0.05) and glycosaminoglycan (GAG) release (p < 0.05) compared to the control group. Furthermore, upregulation of MMP1, MMP13, and ADAMTS5 was observed in both nucleus pulposus (NP) and annulus fibrosus (AF) tissues of the repetitive one strike group (p < 0.05). The one strike group exhibited annulus fibrosus clefts but showed no gene expression changes compared to the control group. Conclusions: This study shows that repetitive violent injuries lead to the degeneration of a healthy bovine IVDs, thereby providing new insights into early-stage disc degeneration.

Identification of immunodiagnostic blood biomarkers associated with spinal cord injury severity.

Blood always shows some immune changes after spinal cord injury (SCI), and detection of such changes in blood may be helpful for diagnosis and treatment of SCI. However, studies to date on blood immune changes after SCI in humans are not comprehensive. Therefore, to obtain the characteristics of blood immune changes and immunodiagnostic blood biomarkers of SCI and its different grades, a human blood transcriptome sequencing dataset was downloaded and analyzed to obtain differentially expressed immune-related genes (DEIGs), related functions and signaling pathways related to SCI and its various grades. Characteristic biomarkers of SCI and its different grades were identified by using weighted gene coexpression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) logistic regression. Expression of biomarkers was verified through experiments. The area under the curve (AUC) of biomarkers was calculated to evaluate their diagnostic value, and differences in immune cell content were examined. In this study, 17 kinds of immune cells with different contents between the SCI group and healthy control (HC) group were identified, with 7 immune cell types being significantly increased. Differences in the content of immune cells between different grades of SCI and the HC group were also discovered. DEIGs were identified, with alteration in some immune-related signaling pathways, vascular endothelial growth factor signaling pathways, and axon guidance signaling pathways. The SCI biomarkers identified and those of American Spinal Injury Society Impairment Scale (AIS) A and AIS D of SCI have certain diagnostic sensitivity. Analysis of the correlation of immune cells and biomarkers showed that biomarkers of SCI, AIS A grade and AIS D grade correlated positively or negatively with some immune cells. CKLF, EDNRB, FCER1G, SORT1, and TNFSF13B can be used as immune biomarkers for SCI. Additionally, GDF11and HSPA1L can be used as biomarkers of SCI AIS A grade; PRKCA and CMTM2 can be used as biomarkers of the SCI AIS D grade. Detecting expression of these putative biomarkers and changes in related immune cells may be helpful for predicting the severity of SCI.

Deciphering postnatal limb development at single-cell resolution.

The early postnatal limb developmental progression bridges embryonic and mature stages and mirrors the pathological remodeling of articular cartilage. However, compared with multitudinous research on embryonic limb development, the early postnatal stage seems relatively unnoticed. Here, a systematic work to portray the postnatal limb developmental landscape was carried out by characterization of 19,952 single cells from murine hindlimbs at 4 postnatal stages using single-cell RNA sequencing technique. By delineation of cell heterogeneity, the candidate progenitor sub-clusters marked by Cd34 and Ly6e were discovered in articular cartilage and enthesis, and three cellular developmental branches marked by Col10a1, Spp1, and Tnni2 were reflected in growth plate. The representative transcriptomes and developmental patterns were intensively explored, and the key regulation mechanisms as well as evolvement in osteoarthritis were discussed. Above all, these results expand horizons of postnatal limb developmental biology and reach the interconnections between limb development, remodeling, and regeneration.