Risk factors and predictive model of cerebral edema after road traffic accidents-related traumatic brain injury.

PURPOSE: Cerebral edema (CE) is the main secondary injury following traumatic brain injury (TBI) caused by road traffic accidents (RTAs). It is challenging to be predicted timely. In this study, we aimed to develop a prediction model for CE by identifying its risk factors and comparing the timing of edema occurrence in TBI patients with varying levels of injuries. METHODS: This case control study included 218 patients with TBI caused by RTAs. The cohort was divided into CE and non-CE groups, according to CT results within 7 days. Demographic data, imaging data, and clinical data were collected and analyzed. Quantitative variables that follow normal distribution were presented as mean ± standard deviation, those that do not follow normal distribution were presented as median and quartiles. Categorical variables were expressed as percentages. The Chi-square test and logistic regression analysis were used to identify risk factors for CE. Logistic curve fitting was performed to predict the time to secondary CE in TBI patients with different levels of injuries. The efficacy of the model was evaluated using the receiver operator characteristic curve. RESULTS: According to the study, almost half (47.3%) of the patients were found to have CE. The risk factors associated with CE were bilateral frontal lobe contusion, unilateral frontal lobe contusion, cerebral contusion, subarachnoid hemorrhage, and abbreviated injury scale (AIS). The odds ratio values for these factors were 7.27 (95% CI: 2.08 - 25.42, p = 0.002), 2.85 (95% CI: 1.11 - 7.31, p = 0.030), 2.62 (95% CI: 1.12 - 6.13, p = 0.027), 2.44 (95% CI: 1.25 - 4.76, p = 0.009), and 1.5 (95% CI: 1.10 - 2.04, p = 0.009), respectively. We also observed that patients with mild/moderate TBI (AIS ≤ 3) had a 50% probability of developing CE 19.7 h after injury (χ2 = 13.82, adjusted R2 = 0.51), while patients with severe TBI (AIS > 3) developed CE after 12.5 h (χ2 = 18.48, adjusted R2 = 0.54). Finally, we conducted a receiver operator characteristic curve analysis of CE time, which showed an area under the curve of 0.744 and 0.672 for severe and mild/moderate TBI, respectively. CONCLUSION: Our study found that the onset of CE in individuals with TBI resulting from RTAs was correlated with the severity of the injury. Specifically, those with more severe injuries experienced an earlier onset of CE. These findings suggest that there is a critical time window for clinical intervention in cases of CE secondary to TBI.

Peptidase inhibitor 16 promotes proliferation of pancreatic ductal adenocarcinoma cells through OASL signaling.

Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive cancer with a poor prognosis and a 5-year survival rate of less than 11%. As a member of the CAP superfamily of proteins, the role of peptidase inhibitor 16 (Pi16) in tumor progression is still unclear. Immunohistochemistry and quantitative RT-PCR methods were used to detect the expression levels of Pi16 protein and mRNA in PDAC patients. CRISPR/Cas9 technology was used to knock out the expression of Pi16 in PDAC cell lines. In vivo and in vitro experiments were used to verify the effect of Pi16 on PDAC proliferation ability. By RNA sequencing, we found that oligoadenylate synthetase L (OASL) can serve as a potential downstream target of Pi16. The expression of Pi16 was higher in PDAC tissues than in matched adjacent tissues. High expression of Pi16 was associated with PDAC progression and poor prognosis. Overexpression of Pi16 could promote the proliferation of PDAC cells in vitro and in vivo. Bioinformatics analysis and coimmunoprecipitation assays showed that Pi16 could bind to OASL. Moreover, the functional recovery test confirmed that Pi16 could promote the proliferation of PDAC via OASL. Our present study demonstrates that Pi16 might participate in the occurrence and development of PDAC by regulating cell proliferation by binding to OASL, indicating that Pi16 might be a promising novel therapeutic target for PDAC.

miR-460b-5p promotes proliferation and differentiation of chicken myoblasts and targets RBM19 gene.

The meat production of broilers is crucial to economic benefits of broiler industries, while the slaughter performance of broilers is directly determined by skeletal muscle development. Hence, the broiler breeding for growth traits shows a great importance. As a kind of small noncoding RNA, microRNA (miRNA) can regulate the expression of multiple genes and perform a wide range of regulation in organisms. Currently, more and more studies have confirmed that miRNAs are closely associated with skeletal muscle development of chickens. Based on our previous miR-seq analysis (accession number: PRJNA668199), miR-460b-5p was screened as one of the key miRNAs probably involved in the growth regulation of chickens. However, the regulatory effect of miR-460b-5p on the development of chicken skeletal muscles is still unclear. Therefore, miR-460b-5p was further used for functional validation at the cellular level in this study. The expression pattern of miR-460b-5p was investigated in proliferation and differentiation stages of chicken primary myoblasts. It was showed that the expression level of miR-460b-5p gradually decreased from the proliferation stage (GM 50%) to the lowest at 24 h of differentiation. As differentiation proceeded, miR-460b-5p expression increased significantly, reaching the highest and stabilizing at 72 h and 96 h of differentiation. Through mRNA quantitative analysis of proliferation marker genes, CCK-8 and Edu assays, miR-460b-5p was found to significantly facilitate the transition of myoblasts from G1 to S phase and promote chicken myoblast proliferation. mRNA and protein quantitative analysis of differentiation marker genes, as well as the indirect immunofluorescence results of myotubes, revealed that miR-460b-5p significantly stimulated myotube development and promote chicken myoblast differentiation. In addition, the target relationship was validated for miR-460b-5p according to the dual-luciferase reporter assay and mRNA quantitative analysis, which indicates that miR-460b-5p was able to regulate RBM19 expression by specifically binding to the 3' UTR of RBM19. In summary, miR-460b-5p has positive regulatory effects on the proliferation and differentiation of chicken myoblasts, and RBM19 is a target gene of miR-460b-5p.

Operando Spectroscopy Observation of Mo Clusters-Ti3 C2 TX Catalyst/Support Interface's Dynamic Evolution in Hydrogen Evolution Reaction.

The interaction between catalyst and support plays an important role in electrocatalytic hydrogen evolution (HER), which may explain the improvement in performance by phase transition or structural remodeling. However, the intrinsic behavior of these catalysts (dynamic evolution of the interface under bias, structural/morphological transformation, stability) has not been clearly monitored, while the operando technology does well in capturing the dynamic changes in the reaction process in real time to determine the actual active site. In this paper, nitrogen-doped molybdenum atom-clusters on Ti3 C2 TX (MoACs /N-Ti3 C2 TX ) is used as a model catalyst to reveal the dynamic evolution of MoAcs on Ti3 C2 TX during the HER process. Operando X-ray absorption structure (XAS) theoretical calculation and in situ Raman spectroscopy showed that the Mo cluster structure evolves to a 6-coordinated monatomic Mo structure under working conditions, exposing more active sites and thus improving the catalytic performance. It shows excellent HER performance comparable to that of commercial Pt/C, including an overpotential of 60 mV at 10 mA cm-2 , a small Tafel slope (56 mV dec-1 ), and high activity and durability. This study provides a unique perspective for investigating the evolution of species, interfacial migration mechanisms, and sources of activity-enhancing compounds in the process of electroreduction.

Gut microbiome-derived ammonia modulates stress vulnerability in the host.

Ammonia has been long recognized as a metabolic waste product with well-known neurotoxic effects. However, little is known about the beneficial function of endogenous ammonia. Here, we show that gut ammonia links microbe nitrogen metabolism to host stress vulnerability by maintaining brain glutamine availability in male mice. Chronic stress decreases blood ammonia levels by altering gut urease-positive microbiota. A representative urease-producing strain, Streptococcus thermophilus, can reverse depression-like behaviours induced by gut microbiota that was altered by stress, whereas pharmacological inhibition of gut ammonia production increases stress vulnerability. Notably, abnormally low blood ammonia levels limit the brain's availability of glutamine, a key metabolite produced by astrocytes that is required for presynaptic γ-aminobutyric acid (GABA) replenishment and confers stress vulnerability through cortical GABAergic dysfunction. Of therapeutic interest, ammonium chloride (NH4Cl), a commonly used expectorant in the clinic, can rescue behavioural abnormalities and GABAergic deficits in mouse models of depression. In sum, ammonia produced by the gut microbiome can help buffer stress in the host, providing a gut-brain signalling basis for emotional behaviour.

Cell type-specific NRBF2 orchestrates autophagic flux and adult hippocampal neurogenesis in chronic stress-induced depression.

Dysfunctional autophagy and impairment of adult hippocampal neurogenesis (AHN) each contribute to the pathogenesis of major depressive disorder (MDD). However, whether dysfunctional autophagy is linked to aberrant AHN underlying MDD remains unclear. Here we demonstrate that the expression of nuclear receptor binding factor 2 (NRBF2), a component of autophagy-associated PIK3C3/VPS34-containing phosphatidylinositol 3-kinase complex, is attenuated in the dentate gyrus (DG) under chronic stress. NRBF2 deficiency inhibits the activity of the VPS34 complex and impairs autophagic flux in adult neural stem cells (aNSCs). Moreover, loss of NRBF2 disrupts the neurogenesis-related protein network and causes exhaustion of aNSC pool, leading to the depression-like phenotype. Strikingly, overexpressing NRBF2 in aNSCs of the DG is sufficient to rescue impaired AHN and depression-like phenotype of mice. Our findings reveal a significant role of NRBF2-dependent autophagy in preventing chronic stress-induced AHN impairment and suggest the therapeutic potential of targeting NRBF2 in MDD treatment.

BNIP3L/NIX-mediated mitophagy alleviates passive stress-coping behaviors induced by tumor necrosis factor-α.

Recent studies based on animal models of various neurological disorders have indicated that mitophagy, a selective autophagy that eliminates damaged and superfluous mitochondria through autophagic degradation, may be involved in various neurological diseases. As an important mechanism of cellular stress response, much less is known about the role of mitophagy in stress-related mood disorders. Here, we found that tumor necrosis factor-α (TNF-α), an inflammation cytokine that plays a particular role in stress responses, impaired the mitophagy in the medial prefrontal cortex (mPFC) via triggering degradation of an outer mitochondrial membrane protein, NIP3-like protein X (NIX). The deficits in the NIX-mediated mitophagy by TNF-α led to the accumulation of damaged mitochondria, which triggered synaptic defects and behavioral abnormalities. Genetic ablation of NIX in the excitatory neurons of mPFC caused passive coping behaviors to stress, and overexpression of NIX in the mPFC improved TNF-α-induced synaptic and behavioral abnormalities. Notably, ketamine, a rapid on-set and long-lasting antidepressant, reversed the TNF-α-induced behavioral abnormalities through activation of NIX-mediated mitophagy. Furthermore, the downregulation of NIX level was also observed in the blood of major depressive disorder patients and the mPFC tissue of animal models. Infliximab, a clinically used TNF-α antagonist, alleviated both chronic stress- and inflammation-induced behavioral abnormalities via restoring NIX level. Taken together, these results suggest that NIX-mediated mitophagy links inflammation signaling to passive coping behaviors to stress, which underlies the pathophysiology of stress-related emotional disorders.

Adaptor protein MyD88 confers the susceptibility to stress via amplifying immune danger signals.

Increasing evidence supports the pathogenic role of neuroinflammation in psychiatric diseases, including major depressive disorder (MDD) and neuropsychiatric symptoms of Coronavirus disease 2019 (COVID-19); however, the precise mechanism and therapeutic strategy are poorly understood. Here, we report that myeloid differentiation factor 88 (MyD88), a pivotal adaptor that bridges toll-like receptors to their downstream signaling by recruiting the signaling complex called 'myddosome', was up-regulated in the medial prefrontal cortex (mPFC) after exposure to chronic social defeat stress (CSDS) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. The inducible expression of MyD88 in the mPFC primed neuroinflammation and conferred stress susceptibility via amplifying immune danger signals, such as high-mobility group box 1 and SARS-CoV-2 spike protein. Overexpression of MyD88 aggravated, whereas knockout or pharmacological inhibition of MyD88 ameliorated CSDS-induced depressive-like behavior. Notably, TJ-M2010-5, a novel synthesized targeting inhibitor of MyD88 dimerization, alleviated both CSDS- and SARS-CoV-2 spike protein-induced depressive-like behavior. Taken together, our findings indicate that inhibiting MyD88 signaling represents a promising therapeutic strategy for stress-related mental disorders, such as MDD and COVID-19-related neuropsychiatric symptoms.

Microglia-dependent excessive synaptic pruning leads to cortical underconnectivity and behavioral abnormality following chronic social defeat stress in mice.

Synapse loss in medial prefrontal cortex (mPFC) has been implicated in stress-related mood disorders, such as depression. However, the exact effect of synapse elimination in the depression and how it is triggered are largely unknown. Through repeated longitudinal imaging of mPFC in the living brain, we found both presynaptic and postsynaptic components were declined, together with the impairment of synapse remodeling and cross-synaptic signal transmission in the mPFC during chronic stress. Meanwhile, chronic stress also induced excessive microglia phagocytosis, leading to engulfment of excitatory synapses. Further investigation revealed that the elevated complement C3 during the stress acted as the tag of synapses to be eliminated by microglia. Besides, chronic stress induced a reduction of the connectivity between the mPFC and neighbor regions. C3 knockout mice displayed significant reduction of synaptic pruning and alleviation of disrupted functional connectivity in mPFC, resulting in more resilience to chronic stress. These results indicate that complement-mediated excessive microglia phagocytosis in adulthood induces synaptic dysfunction and cortical hypo-connectivity, leading to stress-related behavioral abnormality.

SVCT2-mediated ascorbic acid uptake buffers stress responses via DNA hydroxymethylation reprogramming of S100 calcium-binding protein A4 gene.

Vitamin C, a key antioxidant in the central nervous system, cycles between ascorbic acid and dehydroascorbic acid under pathophysiological conditions. Clinical evidence supports that the absence of vitamin C may be linked to depressive symptoms, but much less is known about the mechanism. Herein, we show that chronic stress disrupts the expression of ascorbic acid transporter, sodium-dependent vitamin C transport 2, and induces a deficiency in endogenous ascorbic acid in the medial prefrontal cortex, leading to depressive-like behaviors by disturbing redox-dependent DNA methylation reprogramming. Attractively, ascorbic acid (100 mg/kg-1000 mg/kg, intraperitoneal injection, as bioequivalent of an intravenous drip dose of 0.48 g-4.8 g ascorbic acid per day in humans) produces rapid-acting antidepressant effects via triggering DNA demethylation catalyzed by ten-eleven translocation dioxygenases. In particular, the mechanistic studies by both transcriptome sequencing and methylation sequencing have shown that S100 calcium binding protein A4, a potentially protective factor against oxidative stress and brain injury, mediates the antidepressant activity of ascorbic acid via activating erb-b2 receptor tyrosine kinase 4 (ErbB4)-brain derived neurotrophic factor (BDNF) signaling pathway. Overall, our findings reveal a novel nutritional mechanism that couples stress to aberrant DNA methylation underlying depressive-like behaviors. Therefore, application of vitamin C may be a potential strategy for the treatment of depression.

[Effects of cultivating Coptis chinensis and Paris polyphylla on soil microarthropod communities.] / 种植黄连和重楼对小型土壤节肢动物群落的影响.

In recent years, the area of herbal medicine planting is rapidly increasing. The effects of planting herbal medicines on soil invertebrate communities are still unclear. To reveal the effects of planting different herbal medicines on the soil microarthropod communities, soil microarthropods in two fields of planting Coptis chinensis and Paris polyphylla for 3-year and 5-year, respectively, were investigated in Pengzhou, Chengdu in July 2020. A total of 526 individuals of soil microarthropods were recorded and classified into 4 classes, 17 orders, 69 families, and 98 genera or taxonomic groups. The communities were dominated by Isotoma, Piatynothrus, Folsomia, and Paranura. The community structure of soil microarthropods differed obviously among the two herbal medicine fields, with the main influencing taxonomic groups of Proisotoma, Ocesobates and Epicridae. The total taxonomic group richness of soil microarthropods were richer in C. chinensis field than P. polyphylla field. There was no significant difference in the abundance and diversity index between the two fields. With the increases of cultivating years, the abundance of soil microarthropods in C. chinensis field declined significantly, and Shannon index increased significantly in P. polyphylla field. The redundancy analysis showed that the community structure of soil microarthropods was mainly affected by soil available N, pH, total K, and available K. It suggested that the effects of cultivating herbal medicines on soil microarthropod communities differed between herbal medicine species. Therefore, we recommended to intercrop C. chinensis and P. polyphylla for maintaining the stability of soil microarthropod diversity and promoting ecosystem function.

Comparative Analysis of miRNA Expression Profiles in Skeletal Muscle of Bian Chickens at Different Embryonic Ages.

MicroRNAs (miRNAs) are widely involved in the growth and development of skeletal muscle through the negative regulation of target genes. In order to screen out the differentially expressed miRNAs (DEMs) associated with skeletal muscle development of Bian chickens at different embryonic ages, we used the leg muscles of fast-growing and slow-growing Bian chickens at the 14th and 20th embryonic ages (F14, F20, S14 and S20) for RNA-seq. A total of 836 known miRNAs were identified, and 121 novel miRNAs were predicted. In the F14 vs. F20 comparison group, 127 DEMs were screened, targeting a total of 2871 genes, with 61 miRNAs significantly upregulated and 66 miRNAs significantly downregulated. In the S14 vs. S20 comparison group, 131 DEMs were screened, targeting a total of 3236 genes, with 60 miRNAs significantly upregulated and 71 miRNAs significantly downregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the predicted target genes were significantly enriched in 706 GO terms and 6 KEGG pathways in the F14 vs. F20 group and 677 GO terms and 5 KEGG pathways in the S14 vs. S20 group. According to the interaction network analysis, we screened five coexpressed DEMs (gga-miR-146a-3p, gga-miR-2954, gga-miR-34a-5p, gga-miR-1625-5p and gga-miR-18b-3p) with the highest connectivity degree with predicted target genes between the two comparison groups, and five hub genes (HSPA5, PKM2, Notch1, Notch2 and RBPJ) related to muscle development were obtained as well. Subsequently, we further identified nine DEMs (gga-let-7g-3p, gga-miR-490-3p, gga-miR-6660-3p, gga-miR-12223-5p, novel-miR-327, gga-miR-18a-5p, gga-miR-18b-5p, gga-miR-34a-5p and gga-miR-1677-3p) with a targeting relationship to the hub genes, suggesting that they may play important roles in the muscle development of Bian chickens. This study reveals the miRNA differences in skeletal muscle development between 14- and 20-day embryos of Bian chickens from fast- and slow-growing groups and provides a miRNA database for further studies on the molecular mechanisms of the skeletal muscle development in Bian chickens.

Electrode-Electrolyte Interfacial Chemistry Modulation for Ultra-High Rate Sodium-Ion Batteries.

Sodium-ion batteries capable of operating at rate and temperature extremes are highly desirable, but elusive due to the dynamics and thermodynamics limitations. Herein, a strategy of electrode-electrolyte interfacial chemistry modulation is proposed. The commercial hard carbon demonstrates superior rate performance with 212 mAh g-1 at an ultra-high current density of 5 A g-1 in the electrolyte with weak ion solvation/desolvation, which is much higher than those in common electrolytes (nearly no capacity in carbonate-based electrolytes). Even at -20 °C, a high capacity of 175 mAh g-1 (74 % of its room-temperature capacity) can be maintained at 2 A g-1 . Such an electrode retains 90 % of its initial capacity after 1000 cycles. As proven, weak ion solvation/desolvation of tetrahydrofuran greatly facilitates fast-ion diffusion at the SEI/electrolyte interface and homogeneous SEI with well-distributed NaF and organic components ensures fast Na+ diffusion through the SEI layer and a stable interface.

Composition and assembly of the bacterial community in the overlying waters of the coral reef of China's Xisha Islands.

Coral reef ecosystems are one of the most diverse and productive habitats on Earth. Microbes in the reef-overlying waters are key players in maintaining this ecosystem through regulating biogeochemical and ecological processes. However, the composition structure and assembly mechanism of microbial community in the reef-overlying waters remain largely unknown. In the present study, the bacterial communities from the overlying waters of atolls and fringing reefs as well as the surface waters of the adjacent open ocean of the Xisha Islands in the South China Sea were investigated using 16S rRNA high-throughput sequencing combined with a size-fractionation strategy. The results showed that environments of all sampling stations were similar, characterized by an almost complete lack of inorganic nutrients such as nitrogen and phosphorus. Proteobacteria, Cyanobacteria and Bacteroidetes were the dominant phyla, and Synechococcus was most abundant at the genus level in both large fraction (LF; 1.6-200 µm) and small fraction (SF; 0.2-1.6 µm) communities. Only a slight difference in community composition between LF and SF samples was observed. The bacterial communities among the three habitat types showed noticeable differences, and the bacterial composition among the atoll reefs was more varied than that among the fringing reefs. The similarity of bacterial communities significantly declined with the increasing geographic distance, and stochastic processes were more important than deterministic processes in bacterial community assembly. This study sheds lights on the bacterial biodiversity of coral reefs and the importance of stochastic process in structuring bacterial communities.

Association Between Serum Vitamins and the Risk of Alzheimer's Disease in Chinese Population.

BACKGROUND: Alzheimer's disease (AD) is a chronic and fatal neurodegenerative disease; accumulating evidence suggests that vitamin deficiency is associated with the risk of AD. However, studies attempting to elucidate the relationship between vitamins and AD varied widely. OBJECTIVE: This study aimed to investigate the relationship between serum vitamin levels and AD in a cohort of the Chinese population. METHODS: A total of 368 AD patients and 574 healthy controls were recruited in this study; serum vitamin A, B1, B6, B9, B12, C, D, and E were measured in all participants. RESULTS: Compared with the controls, vitamin B2, B9, B12, D, and E were significantly reduced in AD patients. Lower levels of vitamin B2, B9, B12, D, and E were associated with the risk of AD. After adjusting for age and gender, low levels of vitamin B2, B9, and B12 were still related to the risk of AD. In addition, a negative correlation was determined between vitamin E concentration and Activity of Daily Living Scale score while no significant association was found between serum vitamins and age at onset, disease duration, Mini-Mental State Examination, and Neuropsychiatric Inventory Questionnaire score. CONCLUSION: We conclude that lower vitamin B2, B9, B12, D, and E might be associated with the risk of AD, especially vitamin B2, B9, and B12. And lower vitamin E might be related to severe ability impairment of daily activities.

N-acetylcysteine facilitates extinction of cued fear memory in rats via reestablishing basolateral amygdala glutathione homeostasis.

Individual differences in the development of uncontrollable fear in response to traumatic stressors have been observed in clinic, but the underlying mechanisms remain unknown. In the present study we first conducted a meta-analysis of published clinical data and found that malondialdehyde, an oxidative stress biomarker, was significantly elevated in the blood of patients with fear-related anxiety disorders. We then carried out experimental study in rats subjected to fear conditioning. We showed that reestablishing redox homeostasis in basolateral amygdale (BLA) after exposure to fear stressors determined the capacity of learned fear inhibition. Intra-BLA infusion of buthionine sulfoximine (BSO) to deplete the most important endogenous antioxidant glutathione (GSH) blocked fear extinction, whereas intra-BLA infusion of dithiothreitol or N-acetylcysteine (a precursor of GSH) facilitated extinction. In electrophysiological studies conducted on transverse slices, we showed that fear stressors induced redox-dependent inhibition of NMDAR-mediated synaptic function, which was rescued by extinction learning or reducing agents. Our results reveal a novel pharmacological strategy for reversing impaired fear inhibition and highlight the role of GSH in the treatment of psychiatric disorders.

Growth Factors and Their Roles in Multiple Sclerosis Risk.

Background: Previous studies have suggested essential roles of growth factors on the risk of Multiple Sclerosis (MS), but it remains undefined whether the effects are causal. Objective: We applied Mendelian randomization (MR) approaches to disentangle the causal relationship between genetically predicted circulating levels of growth factors and the risk of MS. Methods: Genetic instrumental variables for fibroblast growth factor (FGF) 23, growth differentiation factor 15 (GDF15), insulin growth factor 1 (IGF1), insulin-like growth factor binding proteins 3 (IGFBP3) and vascular endothelial growth factor (VEGF) were obtained from up-to-date genome-wide association studies (GWAS). Summary-level statistics of MS were obtained from the International Multiple Sclerosis Genetics Consortium, incorporating 14,802 subjects with MS and 26,703 healthy controls of European ancestry. Inverse-variance weighted (IVW) MR was used as the primary method and multiple sensitivity analyses were employed in this study. Results: Genetically predicted circulating levels of FGF23 were associated with risk of MS. The odds ratio (OR) of IVW was 0.63 (95% confidence interval [CI], 0.49-0.82; p < 0.001) per one standard deviation increase in circulating FGF23 levels. Weighted median estimators also suggested FGF23 associated with lower MS risk (OR = 0.67; 95% CI, 0.51-0.87; p = 0.003). While MR-Egger approach provided no evidence of horizontal pleiotropy (intercept = -0.003, p = 0.95). Results of IVW methods provided no evidence for causal roles of GDF1, IGF1, IGFBP3 and VEGF on MS risks, and additional sensitivity analyses confirmed the robustness of these null findings. Conclusion: Our results implied a causal relationship between FGF23 and the risk of MS. Further studies are warranted to confirm FGF23 as a genetically valid target for MS.

Presenilin1 inhibits glioblastoma cell invasiveness via promoting Sortilin cleavage.

BACKGROUND: Alzheimer's disease (AD) and glioblastoma are the most common and devastating diseases in the neurology and neurosurgery departments, respectively. Our previous research reports that the AD-related protein Presenilin1 represses cell proliferation by inhibiting the Wnt/ß-catenin pathway in glioblastoma. However, the function of Presenilin1 and the underlying mechanism need to be further investigated. METHODS: The correlations of two genes were conducted on the R2 microarray platform and CGGA. Wound healing, Transwell assays and glioblastoma transplantation were performed to detect invasion ability. Phalloidin staining was employed to show cell morphology. Proximity ligation assays and protein docking assays were employed to detect two protein locations. We also employed western blotting to detect protein expression. RESULTS: We found that Presenilin1 clearly repressed the migration, invasion and mesenchymal transition of glioblastoma cells. Intriguingly, we observed that the expression of Presenilin1 was positively correlated with Sortilin, which is identified as a pro-invasion molecule in glioma. Furthermore, Presenilin1 interacted with Sortilin at the transmembrane domain and repressed Sortilin expression by cleaving it in glioblastoma cells. First, we found that Sortilin introduced the function of Presenilin1 in phosphorylating ß-catenin and repressing invasion in glioblastoma cells. Last, Presenilin1 stimulation sharply suppressed the invasion and mesenchymal transition of glioblastoma in mouse subcutaneous and intracranial transplantation models. CONCLUSIONS: Our study reveals that Sortilin mediates the regulation of ß-catenin by Presenilin1 and transduces the anti-invasive function of Presenilin1, which may provide novel therapeutic targets for glioblastoma treatment. Video Abstract.

Growth Differentiation Factor 15 Is Associated With Alzheimer's Disease Risk.

BACKGROUND: Previous observational studies have suggested that associations exist between growth differentiation factor 15 (GDF-15) and neurodegenerative diseases. We aimed to investigate the causal relationships between GDF-15 and Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). METHODS: Using summary-level datasets from genome-wide association studies of European ancestry, we performed a two-sample Mendelian randomization (MR) study. Genetic variants significantly associated (p < 5 × 10-8) with GDF-15 were selected as instrumental variables (n = 5). An inverse-variance weighted method was implemented as the primary MR approach, while weighted median, MR-Egger, leave-one-out analysis, and Cochran's Q-test were conducted as sensitivity analyses. All analyses were performed using R 3.6.1 with relevant packages. RESULTS: MR provided evidence for the association of elevated GDF-15 levels with a higher risk of AD (odds ratio = 1.14; 95% confidence interval, 1.04-1.24; p = 0.004). In the reverse direction, Mendelian randomization suggested no causal effect of genetically proxied risk of AD on circulating GDF-15 (p = 0.450). The causal effects of GDF-15 on PD (p = 0.597) or ALS (p = 0.120) were not identified, and the MR results likewise did not support the association of genetic liability to PD or ALS with genetically predicted levels of GDF-15. No evident heterogeneity or horizontal pleiotropy was revealed by multiple sensitivity analyses. CONCLUSION: We highlighted the role of GDF-15 in AD as altogether a promising diagnostic marker and a therapeutic target.