Ultrasound Viscosity Imaging in Breast Lesions: A Multicenter Prospective Study.

RATIONALE AND OBJECTIVES: To explore and validate the clinical value of ultrasound (US) viscosity imaging in differentiating breast lesions by combining with BI-RADS, and then comparing the diagnostic performances with BI-RADS alone. MATERIALS AND METHODS: This multicenter, prospective study enrolled participants with breast lesions from June 2021 to November 2022. A development cohort (DC) and validation cohort (VC) were established. Using histological results as reference standard, the viscosity-related parameter with the highest area under the receiver operating curve (AUC) was selected as the optimal one. Then the original BI-RADS would upgrade or not based on the value of this parameter. Finally, the results were validated in the VC and total cohorts. In the DC, VC and total cohorts, all breast lesions were divided into the large lesion, small lesion and overall groups respectively. RESULTS: A total of 639 participants (mean age, 46 years ± 14) with 639 breast lesions (372 benign and 267 malignant lesions) were finally enrolled in this study including 392 participants in the DC and 247 in the VC. In the DC, the optimal viscosity-related parameter in differentiating breast lesions was calculated to be A'-S2-Vmax, with the AUC of 0.88 (95% CI: 0.84, 0.91). Using > 9.97 Pa.s as the cutoff value, the BI-RADS was then modified. The AUC of modified BI-RADS significantly increased from 0.85 (95% CI: 0.81, 0.88) to 0.91 (95% CI: 0.87, 0.93), 0.85 (95% CI: 0.80, 0.89) to 0.90 (95% CI: 0.85, 0.93) and 0.85 (95% CI: 0.82, 0.87) to 0.90 (95% CI: 0.88, 0.92) in the DC, VC and total cohorts respectively (P < .05 for all). CONCLUSION: The quantitative viscous parameters evaluated by US viscosity imaging contribute to breast cancer diagnosis when combined with BI-RADS.

Dachshund Homolog 1: Unveiling Its Potential Role in Megakaryopoiesis and Bacillus anthracis Lethal Toxin-Induced Thrombocytopenia.

Lethal toxin (LT) is the critical virulence factor of Bacillus anthracis, the causative agent of anthrax. One common symptom observed in patients with anthrax is thrombocytopenia, which has also been observed in mice injected with LT. Our previous study demonstrated that LT induces thrombocytopenia by suppressing megakaryopoiesis, but the precise molecular mechanisms behind this phenomenon remain unknown. In this study, we utilized 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced megakaryocytic differentiation in human erythroleukemia (HEL) cells to identify genes involved in LT-induced megakaryocytic suppression. Through cDNA microarray analysis, we identified Dachshund homolog 1 (DACH1) as a gene that was upregulated upon TPA treatment but downregulated in the presence of TPA and LT, purified from the culture supernatants of B. anthracis. To investigate the function of DACH1 in megakaryocytic differentiation, we employed short hairpin RNA technology to knock down DACH1 expression in HEL cells and assessed its effect on differentiation. Our data revealed that the knockdown of DACH1 expression suppressed megakaryocytic differentiation, particularly in polyploidization. We demonstrated that one mechanism by which B. anthracis LT induces suppression of polyploidization in HEL cells is through the cleavage of MEK1/2. This cleavage results in the downregulation of the ERK signaling pathway, thereby suppressing DACH1 gene expression and inhibiting polyploidization. Additionally, we found that known megakaryopoiesis-related genes, such as FOSB, ZFP36L1, RUNX1, FLI1, AHR, and GFI1B genes may be positively regulated by DACH1. Furthermore, we observed an upregulation of DACH1 during in vitro differentiation of CD34-megakaryocytes and downregulation of DACH1 in patients with thrombocytopenia. In summary, our findings shed light on one of the molecular mechanisms behind LT-induced thrombocytopenia and unveil a previously unknown role for DACH1 in megakaryopoiesis.

Hypermethylation Loci of ZNF671, IRF8, and OTX1 as Potential Urine-Based Predictive Biomarkers for Bladder Cancer.

Bladder cancer (BCa) is a significant health issue and poses a healthcare burden on patients, highlighting the importance of an effective detection method. Here, we developed a urine DNA methylation diagnostic panel for distinguishing between BCa and non-BCa. In the discovery stage, an analysis of the TCGA database was conducted to identify BCa-specific DNA hypermethylation markers. In the validation phase, DNA methylation levels of urine samples were measured with real-time quantitative methylation-specific PCR (qMSP). Comparative analysis of the methylation levels between BCa and non-BCa, along with the receiver operating characteristic (ROC) analyses with machine learning algorithms (logistic regression and decision tree methods) were conducted to develop practical diagnostic panels. The performance evaluation of the panel shows that the individual biomarkers of ZNF671, OTX1, and IRF8 achieved AUCs of 0.86, 0.82, and 0.81, respectively, while the combined yielded an AUC of 0.91. The diagnostic panel using the decision tree algorithm attained an accuracy, sensitivity, and specificity of 82.6%, 75.0%, and 90.9%, respectively. Our results show that the urine-based DNA methylation diagnostic panel provides a sensitive and specific method for detecting and stratifying BCa, showing promise as a standard test that could enhance the diagnosis and prognosis of BCa in clinical settings.

CD8+ T cell response in QuantiFERON-TB Gold Plus testing was associated with tuberculosis recurrence: a 2-year prospective study.

BACKGROUND: Recurrence posed an important challenge to pulmonary tuberculosis (PTB) control in China. The prospective study aimed to identify potential risk factors and to explore the value of QuantiFERON-TB Gold Plus (QFT-Plus) in identifying at-risk individuals with treated prior PTB history. METHODS: All eligible individuals aged ≥18 years who had been diagnosed with PTB before 2016 in Zhongmu County, where with an average level of TB prevalence in China, were included and received baseline survey including chest radiography, QuantiFERON-TB Gold In-Tube (QFT-GIT) and QFT-Plus, then PTB recurrence was tracked through a 2-year follow-up. RESULTS: Half of 1068 (52.34%, 559/1068) included eligible participants were QFT-Plus positive at baseline and 21 of them recurred active TB in 2-year follow-up. Individuals aged ≥ 60 years, who had a recent history of TB and smokers were associated with increased risk of TB recurrence with an adjusted odds ratio (aOR) of 3.97 (95% confidence interval (CI): 1.29-12.24), 7.71 (95% CI: 1.74-34.25) and 4.56 (95% CI: 1.62-12.83), respectively. Compared to QFT-Plus negatives, those who were TB2+/TB1- (aOR = 15.34) exhibited stronger association with the risk of TB recurrence than those who were TB1+/TB2+ (aOR = 6.06). A dose response relationship was also found between the risk of TB recurrence with the baseline level of TB2-TB1 (p for trend < 0.001). CONCLUSIONS: High burden of TB infection and high risk of PTB recurrence were observed in the study population. Those with recent onset of prior TB, elderly smokers and QFT-Plus positives especially with TB2 single positive deserved further attention in active TB surveillance.

A Novel Data Augmentation Approach Using Mask Encoding for Deep Learning-Based Asynchronous SSVEP-BCI.

Deep learning (DL)-based methods have been successfully employed as asynchronous classification algorithms in the steady-state visual evoked potential (SSVEP)-based brain-computer interface (BCI) system. However, these methods often suffer from the limited amount of electroencephalography (EEG) data, leading to overfitting. This study proposes an effective data augmentation approach called EEG mask encoding (EEG-ME) to mitigate overfitting. EEG-ME forces models to learn more robust features by masking partial EEG data, leading to enhanced generalization capabilities of models. Three different network architectures, including an architecture integrating convolutional neural networks (CNN) with Transformer (CNN-Former), time domain-based CNN (tCNN), and a lightweight architecture (EEGNet) are utilized to validate the effectiveness of EEG-ME on publicly available benchmark and BETA datasets. The results demonstrate that EEG-ME significantly enhances the average classification accuracy of various DL-based methods with different data lengths of time windows on two public datasets. Specifically, CNN-Former, tCNN, and EEGNet achieve respective improvements of 3.18%, 1.42%, and 3.06% on the benchmark dataset as well as 11.09%, 3.12%, and 2.81% on the BETA dataset, with the 1-second time window as an example. The enhanced performance of SSVEP classification with EEG-ME promotes the implementation of the asynchronous SSVEP-BCI system, leading to improved robustness and flexibility in human-machine interaction.

Prognostic value and immunological role of PD-L1 gene in pan-cancer.

OBJECTIVE: PD-L1, a target of immune checkpoint blockade, has been proven to take the role of an oncogene in most human tumors. However, the role of PD-L1 in human pan-cancers has not yet been fully investigated. MATERIALS AND METHODS: Pan-cancer analysis was conducted to analyze expression, genetic alterations, prognosis analysis, and immunological characteristics of PD-L1. Estimating the correlation between PD-L1 expression and survival involved using pooled odds ratios and hazard ratios with 95% CI. The Kaplan-Meier (K-M) technique, COX analysis, and receiver operating characteristic (ROC) curves were applied to the survival analysis. Additionally, we investigated the relationships between PD-L1 and microsatellite instability (MSI), tumor mutational burden (TMB), DNA methyltransferases (DNMTs), the associated genes of mismatch repair (MMR), and immune checkpoint biomarkers using Spearman's correlation analysis. Also, immunohistochemical analysis and qRT-PCR were employed in evaluating PD-L1's protein and mRNA expression in pan-caner. RESULTS: PD-L1 showed abnormal mRNA and protein expression in a variety of cancers and predicted prognosis in cancer patients. Furthermore, across a variety of cancer types, the aberrant PD-L1 expression was connected to the MSI, MMR, TMB, drug sensitivity, and tumor immune microenvironment (TIME). Moreover, PD-L1 was significantly correlated with infiltrating levels of immune cells (T cell CD8 + , neutrophil, and so on). CONCLUSION: Our study provides a better theoretical basis and guidance for the clinical treatment of PD-L1.

A Comprehensive Pan-cancer Analysis of the Biological Immunomodulatory Function and Clinical Value of CD27.

Background: CD27 is an immunological checkpoint gene, plays a critical function inInhibition or activation of cancer immunity. The CD27/CD27L axis is its pathway of action. Therefore, our goal was to examine the predictive role of CD27 in the clinical prognosis of 33 cancer types and its functions in cancer progression, as well as explore the link between pan-cancer CD27 gene expression and immune infiltration. Methods: By comprehensive use of datasets and methods from TCGA, cBioPortal, GTEx, HPA, KM-plotter, Spearman, CellMinerTM, R packages and RT-qPCR, we delved deeper into the potential impact of the CD27 on cancer development. These include expression differences, immune infiltration, matrix infiltration, gene mutations, DNA methylation, signaling pathways, TMB, MSI, and prognosis. Also, we explored CD27 interactions with different drugs. Results: The results showed that, mutated CD27 was highly expressed in most cancers. The CD27 showed strong diagnostic value in 4 cancers and marked a positive prognosis for CESC, intracervical adenocarcinoma, HNSC, and endometrial cancer, and a poor prognosis for UVM. In addition, CD27 affects multiple immune and inflammatory signaling pathways and is positively correlated with immune cell infiltration, T cell differentiation, macrophage M1 polarization, stromal infiltration, and drug sensitivity. DNA methylation is involved in CD27 expression in cancer. Conclusion: CD27, which is mutated in cancers and appears widely highly expressed and altered tumor immune invasion and stromal invasion by affecting multiple immune-related and inflammation signaling pathways, plays a significant role in CESC, HNSC, UCEC and UVM, and may be used as a therapeutic target for related cancers.

Intravenous immunoglobulin for treatment of hospitalized COVID-19 patients: an evidence mapping and meta-analysis.

BACKGROUND: The clinical efficacy and safety of intravenous immunoglobulin (IVIg) treatment for COVID-19 remain controversial. This study aimed to map the current status and gaps of available evidence, and conduct a meta-analysis to further investigate the benefit of IVIg in COVID-19 patients. METHODS: Electronic databases were searched for systematic reviews/meta-analyses (SR/MAs), primary studies with control groups, reporting on the use of IVIg in patients with COVID-19. A random-effects meta-analysis with subgroup analyses regarding study design and patient disease severity was performed. Our outcomes of interest determined by the evidence mapping, were mortality, length of hospitalization (days), length of intensive care unit (ICU) stay (days), number of patients requiring mechanical ventilation, and adverse events. RESULTS: We included 34 studies (12 SR/MAs, 8 prospective and 14 retrospective studies). A total of 5571 hospitalized patients were involved in 22 primary studies. Random-effects meta-analyses of very low to moderate evidence showed that there was little or no difference between IVIg and standard care or placebo in reducing mortality (relative risk [RR] 0.91; 95% CI 0.78-1.06; risk difference [RD] 3.3% fewer), length of hospital (mean difference [MD] 0.37; 95% CI - 2.56, 3.31) and ICU (MD 0.36; 95% CI - 0.81, 1.53) stays, mechanical ventilation use (RR 0.92; 95% CI 0.68-1.24; RD 2.8% fewer), and adverse events (RR 0.98; 95% CI 0.84-1.14; RD 0.5% fewer) of patients with COVID-19. Sensitivity analysis using a fixed-effects model indicated that IVIg may reduce mortality (RR 0.76; 95% CI 0.60-0.97), and increase length of hospital stay (MD 0.68; 95% CI 0.09-1.28). CONCLUSION: Very low to moderate certainty of evidence indicated IVIg may not improve the clinical outcomes of hospitalized patients with COVID-19. Given the discrepancy between the random- and fixed-effects model results, further large-scale and well-designed RCTs are warranted.

Chinese expert consensus on the management of patients with hematologic malignancies infected with SARS-CoV-2.

In December 2022, the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became dominant in China due to its high infectivity and lower mortality rate. The risk of critical illness and mortality among patients with hematologic malignancies who contracted SARS-CoV-2 was particularly high. The aim of this study was to draft a consensus to facilitate effective treatments for these patients based on the type and severity of the disease. Following the outbreak of the novel coronavirus in China, a steering committee consisting of experienced hematologists was formed by the Specialized Committee of Oncology and Microecology of the Chinese Anti-Cancer Association. The expert group drafted a consensus on the management and intervention measures for different types of hematologic malignancies based on the clinical characteristics of the Omicron variant of the SARS-CoV-2 infection, along with relevant guidelines and literature. The expert group drafted independent recommendations on several important aspects based on the epidemiology of the Omicron variant in China and the unique vulnerability of patients with hematologic malignancies. These included prophylactic vaccinations for those with hematologic malignancies, the use of plasma from blood donors who recovered from the novel coronavirus infection, the establishment of negative pressure wards, the use of steady-state mobilization of peripheral blood hematopoietic stem cells, the provision of psychological support for patients and medical staff, and a focus on maintaining a healthy intestinal microecology.

Efficient Degradation of Rhodamine B with the BiOCl/Bi2Fe4O9 Heterojunction Photocatalyst.

BiOCl/Bi2Fe4O9 photocatalyst was prepared by a coprecipitation-hydrothermal method. The heterojunction structure generated by the composite of BiOCl and Bi2Fe4O9 reduced the electron-hole recombination efficiency and improved the degradation rate of RhB. At 240 min, 20% BiOCl/Bi2Fe4O9 represented the excellent degradation effect on 10 mg/L RhB; the degradation efficiency reached 99.56%; and the reaction rate constant was 0.01534 min-1, which was 5.76 times and 6.06 times that of Bi2Fe4O9 and BiOCl, respectively. The main active substance of the photocatalytic degradation of dyes was superoxide radical O2-·. Five cycles of the experiment proved the relative stability of BiOCl/Bi2Fe4O9.

Neuronal MeCP2 in the dentate gyrus regulates mossy fiber sprouting of mice with temporal lobe epilepsy.

Sprouting of mossy fibers, one of the most consistent findings in tissue from patients with mesial temporal lobe epilepsy, exhibits several uncommon axonal growth features and has been considered a paradigmatic example of circuit plasticity that occurs in the adult brain. Clarifying the mechanisms responsible may provide new insight into epileptogenesis as well as axon misguidance in the central nervous system. Methyl-CpG-binding protein 2 (MeCP2) binds to methylated genomic DNA to regulate a range of physiological functions implicated in neuronal development and adult synaptic plasticity. However, exploring the potential role of MeCP2 in the documented misguidance of axons in the dentate gyrus has not yet been attempted. In this study, a status epilepticus-induced decrease of neuronal MeCP2 was observed in the dentate gyrus (DG). An essential regulatory role of MeCP2 in the development of functional mossy fiber sprouting (MFS) was confirmed through stereotaxic injection of a recombinant adeno-associated virus (AAV) to up- or down-regulate MeCP2 in the dentate neurons. Chromatin immunoprecipitation sequencing (ChIP-seq) was performed to identify the binding profile of native MeCP2 using micro-dissected dentate tissues. In both dentate tissues and HT22 cell lines, we demonstrated that MeCP2 could act as a transcription repressor on miR-682 with the involvement of the DNA methylation mechanism. Further, we found that miR-682 could bind to mRNA of phosphatase and tensin homolog (PTEN) in a sequence specific manner, thus leading to the suppression of PTEN and excessive activation of mTOR. This study therefore presents a novel epigenetic mechanism by identifying MeCP2/miR-682/PTEN/mTOR as an essential signal pathway in regulating the formation of MFS in the temporal lobe epileptic (TLE) mice. SIGNIFICANCE STATEMENT: Understanding the mechanisms that regulate axon guidance is important for a better comprehension of neural disorders. Sprouting of mossy fibers, one of the most consistent findings in patients with mesial temporal lobe epilepsy, has been considered a paradigmatic example of circuit plasticity in the adult brain. Although abnormal regulation of DNA methylation has been observed in both experimental rodents and humans with epilepsy, the potential role of DNA methylation in this well-documented example of sprouting of dentate axon remains elusive. This study demonstrates an essential role of methyl-CpG-binding protein 2 in the formation of mossy fiber sprouting. The underlying signal pathway has been also identified. The data hence provide new insight into epileptogenesis as well as axon misguidance in the central nervous system.

Platelet-derived circulating soluble P-selectin is sufficient to induce hematopoietic stem cell mobilization.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF)-mediated mobilization of hematopoietic stem cells (HSCs) is a well-established method to prepare HSCs for transplantation nowadays. A sufficient number of HSCs is critical for successful HSC transplantation. However, approximately 2-6% of healthy stem cell donors are G-CSF-poor mobilizers for unknown reasons; thus increasing the uncertainties of HSC transplantation. The mechanism underlining G-CSF-mediated HSC mobilization remains elusive, so detailed mechanisms and an enhanced HSC mobilization strategy are urgently needed. Evidence suggests that P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) are one of the cell-cell adhesion ligand-receptor pairs for HSCs to keep contacting bone marrow (BM) stromal cells before being mobilized into circulation. This study hypothesized that blockage of PSGL-1 and P-selectin may disrupt HSC-stromal cell interaction and facilitate HSC mobilization. METHODS: The plasma levels of soluble P-selectin (sP-sel) before and after G-CSF administration in humans and male C57BL/6J mice were analyzed using enzyme-linked immunosorbent assay. Male mice with P-selectin deficiency (Selp-/-) were further employed to investigate whether P-selectin is essential for G-CSF-induced HSC mobilization and determine which cell lineage is sP-sel derived from. Finally, wild-type mice were injected with either G-CSF or recombinant sP-sel to investigate whether sP-sel alone is sufficient for inducing HSC mobilization and whether it accomplishes this by binding to HSCs and disrupting their interaction with stromal cells in the BM. RESULTS: A significant increase in plasma sP-sel levels was observed in humans and mice following G-CSF administration. Treatments of G-CSF induced a decrease in the level of HSC mobilization in Selp-/- mice compared with the wild-type (Selp+/+) controls. Additionally, the transfer of platelets derived from wild-type mice can ameliorate the defected HSC mobilization in the Selp-/- recipients. G-CSF induces the release of sP-sel from platelets, which is sufficient to mobilize BM HSCs into the circulation of mice by disrupting the PSGL-1 and P-selectin interaction between HSCs and stromal cells. These results collectively suggested that P-selectin is a critical factor for G-CSF-induced HSC mobilization. CONCLUSIONS: sP-sel was identified as a novel endogenous HSC-mobilizing agent. sP-sel injections achieved a relatively faster and more convenient regimen to mobilize HSCs in mice than G-CSF. These findings may serve as a reference for developing and optimizing human HSC mobilization in the future.

Association between antihyperlipidemic agents and the risk of chronic periodontitis in patients with hyperlipidemia: A population-based retrospective cohort study in Taiwan.

BACKGROUND: The lipid-lowering and anti-inflammatory effects of statins and fibrates may ameliorate periodontitis. Patients with hyperlipidemia tend to have a worse periodontal status. This study assessed the association between the use of statins/fibrates and the incidence of chronic periodontitis in patients with hyperlipidemia in Taiwan. METHODS: This retrospective cohort study enrolled patients newly diagnosed with hyperlipidemia between 2001 and 2012 from the 2000 Longitudinal Generation Tracking Database and followed them for 5 years. The study population was divided into four groups: statin monotherapy, fibrate monotherapy, combination therapy (both statins and fibrates), and control (neither statins nor fibrates). Each patient in the treatment group was matched at a ratio of 1:1 with a control. Chronic periodontitis risk was compared in the three study arms by using a Cox proportional hazard model. RESULTS: Chronic periodontitis risk was reduced by 25.7% in the combination therapy group compared with the control group (adjusted hazard ratio [aHR], 0.743; 95% confidence interval (CI), 0.678-0.815). Low dose (<360 cumulative defined daily dose [cDDD]) and shorter duration (<2 years) of statin monotherapy seem to be associated with an increased risk of chronic periodontitis; high dose (≥720 cDDD/≥1080 cDDD) and longer duration (≥3 years) of statin/fibrate monotherapy may be correlated with a lower risk of periodontitis. Hydrophobic statin users had a lower chronic periodontitis risk than hydrophilic statin users. CONCLUSION: Chronic periodontitis risk was lower in patients with hyperlipidemia on combination treatment with statins and fibrates, and the risk decreased when patients used statins or fibrates for >3 years.

Rational Design of Bioactive Materials for Bone Hemostasis and Defect Repair.

Everyday unnatural events such as trauma, accidents, military conflict, disasters, and even medical malpractice create open wounds and massive blood loss, which can be life-threatening. Fractures and large bone defects are among the most common types of injuries. Traditional treatment methods usually involve rapid hemostasis and wound closure, which are convenient and fast but may result in various complications such as nerve injury, deep infection, vascular injury, and deep hematomas. To address these complications, various studies have been conducted on new materials that can be degraded in the body and reduce inflammation and abscesses in the surgical area. This review presents the latest research progress in biomaterials for bone hemostasis and repair. The mechanisms of bone hemostasis and bone healing are first introduced and then principles for rational design of biomaterials are summarized. After providing representative examples of hemostatic biomaterials for bone repair, future challenges and opportunities in the field are proposed.

Improving Generalized Zero-Shot Learning SSVEP Classification Performance From Data-Efficient Perspective.

Generalized zero-shot learning (GZSL) has significantly reduced the training requirements for steady-state visual evoked potential (SSVEP) based brain-computer interfaces (BCIs). Traditional methods require complete class data sets for training, but GZSL allows for only partial class data sets, dividing them into 'seen' (those with training data) and 'unseen' classes (those without training data). However, inefficient utilization of SSVEP data limits the accuracy and information transfer rate (ITR) of existing GZSL methods. To this end, we proposed a framework for more effective utilization of SSVEP data at three systematically combined levels: data acquisition, feature extraction, and decision-making. First, prevalent SSVEP-based BCIs overlook the inter-subject variance in visual latency and employ fixed sampling starting time (SST). We introduced a dynamic sampling starting time (DSST) strategy at the data acquisition level. This strategy uses the classification results on the validation set to find the optimal sampling starting time (OSST) for each subject. In addition, we developed a Transformer structure to capture the global information of input data for compensating the small receptive field of existing networks. The global receptive fields of the Transformer can adequately process the information from longer input sequences. For the decision-making level, we designed a classifier selection strategy that can automatically select the optimal classifier for the seen and unseen classes, respectively. We also proposed a training procedure to make the above solutions in conjunction with each other. Our method was validated on three public datasets and outperformed the state-of-the-art (SOTA) methods. Crucially, we also outperformed the representative methods that require training data for all classes.

Isoflurane-induced reduction in neurogenesis derived from the tertiary dentate matrix.

Anesthetics-induced disruption of dentate neurogenesis in the young brain is strongly suggested to contribute to delayed neurocognitive deficit. In postnatal rodents, the neurogenesis of the dentate gyrus (DG) is sequentially derived from the secondary dentate matrix, tertiary dentate matrix and subgranular zone (SGZ). However, the effects of anesthetics on the dentate neurogenesis derived from specific sites are poorly understood. To trace the new cells generated from the postnatal secondary dentate matrix, peak stage of the tertiary dentate matrix and early stage of the SGZ after isoflurane exposure, mice at postnatal day 1 (P1), P7 and P31 were injected with BrdU at 12 h before the exposure. We found that isoflurane exposure significantly reduced the numbers of proliferating cells (1 day old), immature granule cells (21 days old) or mature granule cells (42 days old) derived from the peak stage of the tertiary dentate matrix and postnatal secondary dentate matrix, but not from the SGZ. Quantitative assessment of BrdU-/BrdU+NeuN-positive cells and cleaved caspase-3 level in the DG indicated that the reduction was correlated with cell loss rather than neuronal differentiation. Mechanistically, we demonstrated that the PI3K/Akt/GSK-3ß pathway enriched by mRNA-sequencing is a requirement for the isoflurane-induced loss of 1-day-old proliferating cells generated from the tertiary dentate matrix. In addition, this study demonstrated that P1 and P7 mice, but not P31 mice exposure to isoflurane resulted in subsequent deficits in performance of the tasks of the Morris Water Maze.

Gliptins normalize posttraumatic hippocampal neurogenesis and restore cognitive function after controlled cortical impact on sensorimotor cortex.

Traumatic brain injury (TBI) often leads to long-term neurocognitive dysfunctions. Adult neurogenesis in the hippocampal dentate gyrus (DG) serves critical functions in cognition but can be disrupted by brain injury and insult in serval forms. In the present study, we explore the cellular and molecular targets of DPP-4 inhibitors (or gliptins) as related to hippocampal function and TBI cognitive sequelae. Two structurally different gliptins, sitagliptin and vildagliptin, were examined using a controlled cortical impact (CCI) model of moderate TBI in mice. Sensorimotor CCI, although distal from the hippocampus, impaired hippocampal-dependent cognition without obvious hippocampal tissue destruction. Neurogenic cell proliferation in the DG was increased accompanied by large numbers of reactive astrocyte. Increased numbers of immature granule cells with abnormal dendritic outgrowth were ectopically localized in the outer granule cell layer (GCL) and hilus. Long-term potentiation of dentate immature granule cells was also impaired. Both sitagliptin and vildagliptin attenuated the CCI-induced ectopic migration of doublecortin-positive immature neurons into the outer GCL and hilus, restored the normal dendritic branching pattern of the immature neurons and prevented astrocyte reactivation. Both gliptins prevented loss of normal synaptic integration in the DG after sensorimotor CCI and improved cognitive behavior. Sensorimotor cortical injury thus results in an abnormal neurogenesis pattern and astrocyte reactivation in the distal hippocampus which appears to contribute to the development of cognitive dysfunction after TBI. DPP-4 inhibitors prevent astrocyte reactivation, normalize the posttraumatic hippocampal neurogenesis and help to maintain normal electrophysiology in the DG with positive behavioral effect in a mouse model.

The effectiveness of postoperative exercise based on gait analysis compared with conventional exercise in patients with lumbar spinal stenosis: A randomized clinical trial.

BACKGROUND: Despite being used as a program of postoperative rehabilitation, few randomized controlled trials have compared the effectiveness of postoperative exercise based on gait analysis in patients with lumbar spinal stenosis (LSS). OBJECTIVE: To investigate the effectiveness of postoperative exercise based on gait analysis in patients with LSS and to compare it with the effectiveness of conventional exercise. METHODS: This was a double-blind, randomized clinical trial. Sixty-eight participants with LSS were randomly assigned to one of two groups. After receiving a standardized surgical procedure, the observation group received exercises based on 3-D gait analysis, and the control group received empirical physiotherapy containing 4 basic interventions. Both groups took a one-hour session twice daily for 2 weeks. The Oswestry Disability Index (ODI) scale and the Visual Analog Scale (VAS) were measured before and 2 weeks and 6 months after intervention. The gait indicators were measured before and 6 months after intervention. RESULTS: At baseline, there were no significant differences in the ODI, VAS or absolute symmetry index (ASI) of the gait variables between the observation group and the control group. However, at 6 months, pain intensity, walking, standing, social life and summary scores of ODI and VAS of the leg demonstrated significant differences (p< 0.05, respectively) between groups, and the observation group had greater reductions in ASI of stride length, hip flexion, knee flexion and ankle dorsiflexion compared with the control group (p< 0.05, respectively). CONCLUSIONS: The postoperative rehabilitation scheme based on gait analysis resulted in significant short- to medium-term improvements in pain intensity, walking, standing, social life and the summary score of ODI, VAS of leg and symmetry of stride length, hip flexion, knee flexion and ankle dorsiflexion compared with empirical exercise in patients with LSS.

Metabolomic and transcriptomic analyses reveal the effects of grafting on blood orange quality.

Introduction: Blood orange (Citrus sinensis L.) is a valuable source of nutrition because it is enriched in anthocyanins and has high organoleptic properties. Grafting is commonly used in citriculture and has crucial effects on various phenotypes of the blood orange, including its coloration, phenology, and biotic and abiotic resistance. Still, the underlying genetics and regulatory mechanisms are largely unexplored. Methods: In this study, we investigated the phenotypic, metabolomic, and transcriptomic profiles at eight developmental stages of the lido blood orange cultivar (Citrus sinensis L. Osbeck cv. Lido) grafted onto two rootstocks. Results and discussion: The Trifoliate orange rootstock provided the best fruit quality and flesh color for Lido blood orange. Comparative metabolomics suggested significant differences in accumulation patterns of metabolites and we identified 295 differentially accumulated metabolites. The major contributors were flavonoids, phenolic acids, lignans and coumarins, and terpenoids. Moreover, transcriptome profiling resulted in the identification of 4179 differentially expressed genes (DEGs), and 54 DEGs were associated with flavonoids and anthocyanins. Weighted gene co-expression network analysis identified major genes associated to 16 anthocyanins. Furthermore, seven transcription factors (C2H2, GANT, MYB-related, AP2/ERF, NAC, bZIP, and MYB) and five genes associated with anthocyanin synthesis pathway (CHS, F3H, UFGT, and ANS) were identified as key modulators of the anthocyanin content in lido blood orange. Overall, our results revealed the impact of rootstock on the global transcriptome and metabolome in relation to fruit quality in lido blood orange. The identified key genes and metabolites can be further utilized for the quality improvement of blood orange varieties.