Comparing the osteogenesis outcomes of different lumbar interbody fusions (A/O/X/T/PLIF) by evaluating their mechano-driven fusion processes.

BACKGROUND: In lumbar interbody fusion (LIF), achieving proper fusion status requires osteogenesis to occur in the disc space. Current LIF techniques, including anterior, oblique, lateral, transforaminal, and posterior LIF (A/O/X/T/PLIF), may result in varying osteogenesis outcomes due to differences in biomechanical characteristics. METHODS: A mechano-regulation algorithm was developed to predict the fusion processes of A/O/X/T/PLIF based on finite element modeling and iterative evaluations of the mechanobiological activities of mesenchymal stem cells (MSCs) and their differentiated cells (osteoblasts, chondrocytes, and fibroblasts). Fusion occurred in the grafting region, and each differentiated cell type generated the corresponding tissue proportional to its concentration. The corresponding osteogenesis volume was calculated by multiplying the osteoblast concentration by the grafting volume. RESULTS: TLIF and ALIF achieved markedly greater osteogenesis volumes than did PLIF and O/XLIF (5.46, 5.12, 4.26, and 3.15 cm3, respectively). Grafting volume and cage size were the main factors influencing the osteogenesis outcome in patients treated with LIF. A large grafting volume allowed more osteoblasts (bone tissues) to be accommodated in the disc space. A small cage size reduced the cage/endplate ratio and therefore decreased the stiffness of the LIF. This led to a larger osteogenesis region to promote osteoblastic differentiation of MSCs and osteoblast proliferation (bone regeneration), which subsequently increased the bone fraction in the grafting space. CONCLUSION: TLIF and ALIF produced more favorable biomechanical environments for osteogenesis than did PLIF and O/XLIF. A small cage and a large grafting volume improve osteogenesis by facilitating osteogenesis-related cell activities driven by mechanical forces.

CREaTor: zero-shot cis-regulatory pattern modeling with attention mechanisms.

Linking cis-regulatory sequences to target genes has been a long-standing challenge. In this study, we introduce CREaTor, an attention-based deep neural network designed to model cis-regulatory patterns for genomic elements up to 2 Mb from target genes. Coupled with a training strategy that predicts gene expression from flanking candidate cis-regulatory elements (cCREs), CREaTor can model cell type-specific cis-regulatory patterns in new cell types without prior knowledge of cCRE-gene interactions or additional training. The zero-shot modeling capability, combined with the use of only RNA-seq and ChIP-seq data, allows for the ready generalization of CREaTor to a broad range of cell types.

[A Novel Three-minute Game-based Cognitive Risk Screening Tool-WeChat Mini-program-based Design and Large-sample Feasibility Studies].

OBJECTIVE: To develop a novel cognitive screening tool for older adults in China. METHODS: "Game-based Cognitive Assessment-3 Minute Version"(G3) was designed and developed based on WeChat mini-program. And its feasibility was analyzed. RESULTS: G3 mini-program contains three one-minute mini digital games and supports users' self-assessment of cognitive functions with instant access to reports. G3 had a good correlation with Montreal Cognitive Assessment Basic (MoCA-B) with Pearson's r =0.611 (P<0.001). Among natural users aged 50 and older (71 179), the G3 initiation and completion rates were 99.55% and 92.28%, respectively. The average time to complete G3 assessments was (278.5±73.73) seconds. CONCLUSIONS: The novel G3 mini-program has good feasibility and usability for older Chinese adults, and can be used for cognitive screening and home self-assessment.

Shanghai Cognitive Screening: A Mobile Cognitive Assessment Tool Using Voice Recognition to Detect Mild Cognitive Impairment and Dementia in the Community.

BACKGROUND: A rapid digital instrument is needed to facilitate community-based screening of mild cognitive impairment (MCI) and Alzheimer's disease (AD) in China. OBJECTIVE: We developed a voice recognition-based cognitive assessment (Shanghai Cognitive Screening, SCS) on mobile devices and evaluated its diagnostic performance. METHODS: Participants (N = 251) including healthy controls (N = 98), subjective cognitive decline (SCD, N = 42), MCI (N = 80), and mild AD (N = 31) were recruited from the memory clinic at Shanghai Sixth People's Hospital. The SCS is fully self-administered, takes about six minutes and measures the function of visual memory, language, and executive function. Participants were instructed to complete SCS tests, gold-standard neuropsychological tests and standardized structural 3T brain MRI. RESULTS: The Cronbach's alpha was 0.910 of the overall scale, indicating high internal consistency. The SCS total score had an AUC of 0.921 to detect AD (sensitivity = 0.903, specificity = 0.945, positive predictive value = 0.700, negative predictive value = 0.986, likelihood ratio = 16.42, number needed for screening utility = 0.639), and an AUC of 0.838 to detect MCI (sensitivity = 0.793, specificity = 0.671, positive predictive value = 0.657, negative predictive value = 0.803, likelihood ratio = 2.41, number needed for screening utility = 0.944). The subtests demonstrated moderate to high correlations with the gold-standard tests from their respective cognitive domains. The SCS total score and its memory scores all correlated positively with relative volumes of the whole hippocampus and almost all subregions, after controlling for age, sex, and education. CONCLUSION: The SCS has good diagnostic accuracy for detecting MCI and AD dementia and has the potential to facilitate large-scale screening in the general community.

Metabolic fate of glucose in the brain of APP/PS1 transgenic mice at 10 months of age: a 13C NMR metabolomic study.

Alzheimer's disease (AD) has been associated with the disturbance of brain glucose metabolism. The present study investigates brain glucose metabolism using 13C NMR metabolomics in combination with intravenous [1-13C]-glucose infusion in APP/PS1 transgenic mouse model of amyloid pathology at 10 months of age. We found that brain glucose was significantly accumulated in APP/PS1 mice relative to wild-type (WT) mice. Reductions in 13C fluxes into the specific carbon sites of tricarboxylic acid (TCA) intermediate (succinate) as well as neurotransmitters (glutamate, glutamine, γ-aminobutyric acid and aspartate) from [1-13C]-glucose were also detected in the brain of APP/PS1 mice. In addition, our results reveal that the 13C-enrichments of the C3 of alanine were significantly lower and the C3 of lactate have a tendency to be lower in the brain of APP/PS1 mice than WT mice. Taken together, the development of amyloid pathology could cause a reduction in glucose utilization and further result in decreases in energy and neurotransmitter metabolism as well as the lactate-alanine shuttle in the brain.

Metabolic alterations in the rat cerebellum following acute middle cerebral artery occlusion, as determined by 1H NMR spectroscopy.

Supratentorial focal ischemia may reduce cerebral blood volume and cerebellar glucose metabolic rate contralateral to the region of ischemia. The present study investigated the effects of middle cerebral artery occlusion (MCAO) on cerebral metabolism in the ischemic cerebral hemisphere and the non­ischemic cerebellum in rats 1, 3, 9 and 24 h following ischemia using ex vivo proton nuclear magnetic resonance (1H NMR) spectroscopy. The results demonstrated that focal ischemia induced increases in the levels of lactate and alanine, and a decrease in succinate, as early as 1 h following ischemia in the left cerebral hemisphere and the right cerebellum. A continuous increase in lactate levels and decrease in creatine levels were detected in both cerebral areas 3 and 24 h post­MCAO. The most obvious difference between the two cerebral areas was that there was no statistically significant difference in N­acetyl aspartate (NAA) levels in the right cerebellum at all time points; however, the amino acid levels of NAA in the left cerebral hemisphere were markedly decreased 3, 9 and 24 h post­MCAO. In addition, an obvious increase in glutamine was observed in the right and left cerebellum at 3, 9 and 24 h post­MCAO. Furthermore, the present study demonstrated that γ­aminobutyric acid levels were decreased at 1 h in the left and right cerebellum and were evidently increased at 24 h in the right cerebellum post­MCAO. In conclusion, supratentorial ischemia has been indicated to affect the activities of the non­ischemic contralateral cerebellum. Therefore, these results suggested that an NMR­based metabonomic approach may be used as a potential means to elucidate cerebral and cerebellar metabolism following MCAO, which may help improve understanding regarding cerebral infarction at a molecular level. Ex vivo 1H NMR analysis may be useful for the assessment of clinical biopsies.

Early Effect of Amyloid ß-Peptide on Hippocampal and Serum Metabolism in Rats Studied by an Integrated Method of NMR-Based Metabolomics and ANOVA-Simultaneous Component Analysis.

Amyloid ß (Aß) deposition has been implicated in the pathogenesis of Alzheimer's disease. However, the early effect of Aß deposition on metabolism remains unclear. In the present study, thus, we explored the metabolic changes in the hippocampus and serum during first 2 weeks of Aß25-35 injection in rats by using an integrated method of NMR-based metabolomics and ANOVA-simultaneous component analysis (ASCA). Our results show that Aß25-35 injection, time, and their interaction had statistically significant effects on the hippocampus and serum metabolome. Furthermore, we identified key metabolites that mainly contributed to these effects. After Aß25-35 injection from 1 to 2 weeks, the levels of lactate, N-acetylaspartate, creatine, and taurine were decreased in rat hippocampus, while an increase in lactate and decreases in LDL/VLDL and glucose were observed in rat serum. Therefore, we suggest that the reduction in energy and lipid metabolism as well as an increase in anaerobic glycolysis may occur at the early stage of Aß25-35 deposition.

High Glucose-Induced PC12 Cell Death by Increasing Glutamate Production and Decreasing Methyl Group Metabolism.

Objective. High glucose- (HG-) induced neuronal cell death is responsible for the development of diabetic neuropathy. However, the effect of HG on metabolism in neuronal cells is still unclear. Materials and Methods. The neural-crest derived PC12 cells were cultured for 72 h in the HG (75 mM) or control (25 mM) groups. We used NMR-based metabolomics to examine both intracellular and extracellular metabolic changes in HG-treated PC12 cells. Results. We found that the reduction in intracellular lactate may be due to excreting more lactate into the extracellular medium under HG condition. HG also induced the changes of other energy-related metabolites, such as an increased succinate and creatine phosphate. Our results also reveal that the synthesis of glutamate from the branched-chain amino acids (isoleucine and valine) may be enhanced under HG. Increased levels of intracellular alanine, phenylalanine, myoinositol, and choline were observed in HG-treated PC12 cells. In addition, HG-induced decreases in intracellular dimethylamine, dimethylglycine, and 3-methylhistidine may indicate a downregulation of methyl group metabolism. Conclusions. Our metabolomic results suggest that HG-induced neuronal cell death may be attributed to a series of metabolic changes, involving energy metabolism, amino acids metabolism, osmoregulation and membrane metabolism, and methyl group metabolism.

NMR-Based Metabolomics Reveal a Recovery from Metabolic Changes in the Striatum of 6-OHDA-Induced Rats Treated with Basic Fibroblast Growth Factor.

Basic fibroblast growth factor (bFGF) has a potential role in the treatment of Parkinson's disease (PD) due to its neurotrophic effect on dopaminergic neurons. To address the metabolic mechanisms of bFGF administration on PD, we have analyzed the metabolic profiles in the striatum of 6-hydroxydopamine (6-OHDA)-induced PD rats after the treatment with bFGF using 1H NMR spectroscopy and partial least squares-discriminant analysis (PLS-DA). In the present study, we found that bFGF treatment can effectively recover PD-induced loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. Metabolomic analyses reveal that PLS-DA failed to discriminate between the control and bFGF groups, indicating that the metabolic difference between these two groups was negligible. However, reliable PLS-DA models can be developed between control and PD groups as well as between PD and bFGF groups, which is attributed to changes in a series of metabolites including GABA, glutamate (Glu), glutamine (Gln), lactate, N-acetylaspartate, creatine, taurine, and myo-inositol. ANOVA results show that the levels of all these metabolites were significantly increased in PD rats relative to normal rats, while PD-induced increase can be significantly reduced to normal levels after bFGF administration. In conclusion, our results suggest that a recovery from PD-induced metabolic disorders may be achieved by bFGF treatment, involving Gln/Glu-GABA cycle, energy metabolism, osmoregulation, and inflammation.

Metabonomic analysis of potential biomarkers and drug targets involved in diabetic nephropathy mice.

Diabetic nephropathy (DN) is one of the lethal manifestations of diabetic systemic microvascular disease. Elucidation of characteristic metabolic alterations during diabetic progression is critical to understand its pathogenesis and identify potential biomarkers and drug targets involved in the disease. In this study, (1)H nuclear magnetic resonance ((1)H NMR)-based metabonomics with correlative analysis was performed to study the characteristic metabolites, as well as the related pathways in urine and kidney samples of db/db diabetic mice, compared with age-matched wildtype mice. The time trajectory plot of db/db mice revealed alterations, in an age-dependent manner, in urinary metabolic profiles along with progression of renal damage and dysfunction. Age-dependent and correlated metabolite analysis identified that cis-aconitate and allantoin could serve as biomarkers for the diagnosis of DN. Further correlative analysis revealed that the enzymes dimethylarginine dimethylaminohydrolase (DDAH), guanosine triphosphate cyclohydrolase I (GTPCH I), and 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase) were involved in dimethylamine metabolism, ketogenesis and GTP metabolism pathways, respectively, and could be potential therapeutic targets for DN. Our results highlight that metabonomic analysis can be used as a tool to identify potential biomarkers and novel therapeutic targets to gain a better understanding of the mechanisms underlying the initiation and progression of diseases.