Tumor-associated macrophages (TAMs) remodel the colorectal cancer (CRC) microenvironment. Yet, findings on the role of TAMs in CRC seem to be contradictory compared with other cancers. FoxP3(+) ...regulatory T (Treg)-cells dominantly infiltrate CRC. However, the underlying molecular mechanism in which TAMs may contribute to the trafficking of Treg-cells to the tumor mass remains unknown.
CRC was either induced by N-methyl-N-nitrosourea (MNU) and H. pylori or established by subcutaneous injection of mouse colorectal tumor cell line (CMT93) in mice. CMT93 cells were co-cultured with primary macrophages in a transwell apparatus. Recruitment of FoxP3 green fluorescence protein positive (FoxP3(GFP+)) Treg-cells was assessed using the IVIS Imaging System or immunofluorescence staining. A role for macrophages in trafficking of Treg-cells and in the development of CRC was investigated in CD11b diphtheria toxin receptor (CD11b-DTR) transgenic C57BL/6J mice in which macrophages can be selectively depleted. Treg-cells remarkably infiltrated solid tumor, and predominantly expressed the homing chemokine receptor (CCR) 6 in the induced CRC model. Both CMT93 cancer cells and macrophages produced a large amount of CCL20, the sole ligand of CCR6 in vitro and in vivo. Injection of recombinant mouse CCL20 into tumor sites promoted its development with a marked recruitment of Treg-cells in the graft CRC model. Conditional macrophage ablation decreased CCL20 levels, blocked Treg-cell recruitment and inhibited tumor growth in CD11b-DTR mice grafted with CMT93.
TAMs recruit CCR6(+) Treg-cells to tumor mass and promote its development via enhancing the production of CCL20 in a CRC mouse model.
Highly sensitive multiplex biomarker detection is critical for the early diagnosis of liver cancer. Here, a surface-enhanced Raman scattering (SERS) frequency-shift immunoassay is developed for ...detection of liver cancer biomarkers α-fetoprotein and Glypican-3 down to subpicomolar concentrations in saline solution. A high temperature modification of the Tollen’s method affords silver nanoparticle films with excellent SERS response upon which ordered domains of Raman reporters are chemisorbed by microcontact printing. Shifts in the reporters SERS spectrum in response to a bound antibody’s biomarker recognition constitutes the frequency shift assay, exhibiting here exceptional sensitivity and specificity and shown to function in fetal calf serum and in the serum of a patient with hepatocellular carcinoma.
Molecular studies in atopic dermatitis (AD) are largely restricted to patients with moderate-to-severe disease.
Our aim was to evaluate skin and blood abnormalities in mild, moderate, and severe AD.
...Skin and blood samples were obtained from 61 patients with AD (20 with mild or limited disease, 17 with moderate disease, and 24 with severe disease) and 20 healthy subjects. Immune and barrier markers were measured in lesional, nonlesional, and healthy skin by quantitative real-time PCR and immunohistochemistry, and in blood by using the OLINK proteomic assay.
Cellular markers of epidermal hyperplasia and T-cell/dendritic cell infiltration were increased in AD tissues of all patients in all severity groups versus in those of controls, whereas downstream TH2 cell–, TH22 cell–, TH1 cell–, and TH17 cell–related mediators demonstrated incremental elevations with increasing disease severity, in both lesional and nonlesional skin. Whereas the levels of the TH2 (IL13, CCL17, and CCL26) and TH22 (IL-22) cytokines were significantly elevated in both AD lesional and nonlesional skin of all patients regardless of the severity of their disease, patients with mild or limited AD showed increases in their levels of TH1 cell (IFNG, CXCL9, and CXCL10) and TH17 cell (IL-17A, CCL20, and CXCL1) markers in lesional but not nonlesional skin. Regulatory T-cell–related mediators (IL-10 and FOXP3) were comparably upregulated in all groups, without displaying the severity-based gradient in other immune axes. Unsupervised clustering aligned samples along a severity spectrum, where nonlesional mild or limited AD skin clustered with the samples from healthy controls. Furthermore, whereas the blood profiles of patients with moderate and severe AD showed gradual increases in the levels of TH1 cell–, TH2 cell–, and TH17 cell–related and atherosclerosis and/or cardiovascular risk (CCL7, FGF21, and IGFBP1) proteins, the blood profiles of patients with mild or limited AD lacked significant differences from those of the controls.
Mild and limited AD show high levels of TH2/TH22 cell activation that is primarily localized to skin lesions and lacks the systemic inflammation of moderate and severe disease.
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Collaborative knowledge construction (CKC) involved students’ sharing of information, improvement of ideas, and construction of collective knowledge. In this process, knowledge extraction and ...analysis can provide valuable insights into students’ knowledge capacities, depths, and levels in order to improve the CKC quality. However, existing studies tended to extract and analyze knowledge from a single perspective (e.g., the number of certain knowledge types and knowledge structures), which failed to demonstrate the complexity and dynamics of knowledge construction and advancement. To fill this gap, this research designed a series of computer-supported collaborative concept mapping (CSCCM) activities to facilitate students’ CKC process and then used an integrated approach (i.e., semantic knowledge analysis combined with learning analytics) to extract, analyze, and understand students’ knowledge characteristics and evolutionary trends. Results demonstrated that compared to the low-performing pairs, the high-performing pairs mainly discussed knowledge related to the course content, and their knowledge evolution trend was relatively stable. Based on the results, this research provided analytical implications to extract, analyze, and understand students’ knowledge and pedagogical implications to promote students’ knowledge construction and advancement.
Abstract
A complete understanding of the structural and functional potential of RNA requires understanding of chemical modifications and non-canonical bases; this in turn requires advances in current ...sequencing methods to be able to sequence not only canonical ribonucleotides, but at the same time directly sequence these non-standard moieties. Here, we present the first direct and modification type-independent RNA sequencing method via introduction of a 2-dimensional hydrophobic end-labeling strategy into traditional mass spectrometry-based sequencing (2D HELS MS Seq) to allow de novo sequencing of RNA mixtures and enhance sample usage efficiency. Our method can directly read out the complete sequence, while identifying, locating, and quantifying base modifications accurately in both single and mixed RNA samples containing multiple different modifications at single-base resolution. Our method can also quantify stoichiometry/percentage of modified RNA versus its canonical counterpart RNA, simulating a real biological sample where modifications exist but may not be 100% at a particular site in the RNA. This method is a critical step towards fully sequencing real complex cellular RNA samples of any type and containing any modification type and can also be used in the quality control of modified therapeutic RNAs.
Acute kidney injury (AKI) is common among hospitalized children and is associated with a poor prognosis. The study sought to develop machine learning-based models for predicting adverse outcomes ...among hospitalized AKI children. We performed a retrospective study of hospitalized AKI patients aged 1 month to 18 years in the Second Xiangya Hospital of Central South University in China from 2015 to 2020. The primary outcomes included major adverse kidney events within 30 days (MAKE30) (death, new renal replacement therapy, and persistent renal dysfunction) and 90-day adverse outcomes (chronic dialysis and death). The state-of-the-art machine learning algorithm, eXtreme Gradient Boosting (XGBoost), and the traditional logistic regression were used to establish prediction models for MAKE30 and 90-day adverse outcomes. The models' performance was evaluated by split-set test. A total of 1394 pediatric AKI patients were included in the study. The incidence of MAKE30 and 90-day adverse outcomes was 24.1% and 8.1%, respectively. In the test set, the area under the receiver operating characteristic curve (AUC) of the XGBoost model was 0.810 (95% CI 0.763-0.857) for MAKE30 and 0.851 (95% CI 0.785-0.916) for 90-day adverse outcomes, The AUC of the logistic regression model was 0.786 (95% CI 0.731-0.841) for MAKE30 and 0.759 (95% CI 0.654-0.864) for 90-day adverse outcomes. A web-based risk calculator can facilitate the application of the XGBoost models in daily clinical practice. In conclusion, XGBoost showed good performance in predicting MAKE30 and 90-day adverse outcomes, which provided clinicians with useful tools for prognostic assessment in hospitalized AKI children.
Stress fields of a lined non-circular tunnel subjected to in situ stress are derived based on the complex variable method and on the assumption that the interface between the liner and surrounding ...rock is full-slip. The basic equations for solving the stress solutions are obtained according to the stress boundary condition along the inner boundary of the lining and the stress and normal displacement continuity conditions along the rock-lining interface. In the solving process, the support delay is also considered. The basic equations can be solved by the power series method, and the stresses in the surrounding rock mass and lining can be calculated. The distributions of the tangential stresses (also known as the circumferential stresses) along the excavation boundary and the inner boundary of the lining and the contact stresses along the rock-lining interface are analysed. An example demonstrates that the results are significantly affected by the number of terms in the power series. When the number of terms is greater than 100, the boundary conditions can be well satisfied, and the results of the stresses and displacements are highly accurate. The tangential stress results along the inner boundary of the lining for the full-slip condition are compared with those for the perfect bond condition, and the analysis indicates that the maximum value of the tangential stress for the full-slip condition is smaller than that for the perfect bond condition, which gives that the full-slip condition is superior to the perfect bond condition. Thus, the carrying capacity of the lining can be increased if sliding materials are installed between the lining and the surrounding rock mass. The analytic solutions are verified using computer simulation software.
•Full-slip contact is considered along the liner-surrounding rock interface.•Power series method is to be used.•The solutions for a lined non-circular tunnel are obtained.•The stresses in the rock and lining have high level of accuracy.•Full-slip contact is superior to the perfect bond case.
Mutations in RPE65 or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis-retinal recycling and cause Leber congenital amaurosis (LCA), the most severe retinal dystrophy in early childhood. We ...used Lratâ»/â», a murine model for LCA, to investigate the mechanism of rapid cone degeneration. Although both M and S cone opsins mistrafficked as reported previously, mislocalized M-opsin was degraded whereas mislocalized S-opsin accumulated in Lratâ»/â» cones before the onset of massive ventral/central cone degeneration. As the ventral and central retina express higher levels of S-opsin than the dorsal retina in mice, our results may explain why ventral and central cones degenerate more rapidly than dorsal cones in Rpe65â»/â» and Lratâ»/â» LCA models. In addition, human blue opsin and mouse S-opsin, but not mouse M-opsin or human red/green opsins, aggregated to form cytoplasmic inclusions in transfected cells, which may explain why blue cone function is lost earlier than red/green-cone function in patients with LCA. The aggregation of short-wavelength opsins likely caused rapid cone degenerations through an endoplasmic reticulum stress pathway, as demonstrated in both the Lratâ»/â» retina and transfected cells. Replacing rhodopsin with S-opsin in Lratâ»/â» rods resulted in mislocalization and aggregation of S-opsin in the inner segment and the synaptic region of rods, ER stress, and dramatically accelerated rod degeneration. Our results demonstrate that cone opsins play a major role in determining the degeneration rate of photoreceptors in LCA.
•The first study to explore the differential patterns of dynamic functional connectivity variability in major depressive disorder (MDD) treated with cognitive behavioral therapy (CBT).•Patients with ...MDD showed abnormal functional connectivity in dorsolateral prefrontal cortex (dlPFC). DLPFC plays an important role in pathophysiological mechanism of MDD.•After CBT, increased dFC variability in dlPFC and precuneus suggests that CBT helped patients suppress redundant thoughts and negative self-focus. As a connecting node, dlPFC participates in the mechanism of action of CBT.
Numerous studies have shown that major depressive disorder (MDD) is characterized by a range of impairments in emotional and cognitive functions that are closely related to abnormalities in brain structure and function. Cognitive behavioral therapy (CBT) can be used as treatment for mild to moderate MDD, which can assist with ameliorating the symptoms. Previous studies have assumed that the internal fluctuations throughout the entire scan are static. However, it has recently been suggested that the brain connectivity is dynamic and relative to continuous rhythmic activity. The effect of dynamic changes in CBT on MDD patients is unknown.
Nineteen first-episode, unmedicated MDD patients and twenty-two healthy controls (HC) participated in the study. The patients received early CBT treatment once a week for 6 weeks. Symptom examinations and magnetic resonance imaging (MRI) scans were performed pre and post treatment. Degree centrality (DC) was used to investigate the whole-brain connectivity differences between patients with MDD and healthy controls, and sliding window correlation analysis was applied to investigate the dynamic changes of functional connectivity among MDD patients treated with CBT. The variance of dynamic functional connectivity (dFC) was calculated to evaluate the temporal variability along the time.
Patients with MDD showed abnormal DC in dorsolateral prefrontal cortex (dlPFC), insula and postcentral gyrus. Correlation analysis revealed that degree centrality of dlPFC was negatively correlated with the course of disease in patients with MDD. Results of dynamic functional connectivity showed that, compared to HC, MDD patients-remained excessively stable in dlPFC and precuneus connectivity, which is associated with emotional cognitive symptoms. After CBT, patients showed increased dFC variability in dlPFC and precuneus (p < 0.01, GRF corrected).
DLPFC plays an important role in pathophysiological mechanism of MDD. CBT helped patients suppress redundant thoughts and negative self-focus. As a connecting node, dlPFC participates in the mechanism of action of CBT.
Data Integrity Auditing (DIA) is a security service for verifying the integrity of outsourced data in Public Cloud Storage (PCS) by users or by Third-Party Auditors (TPAs) on behalf of the users. ...This paper proposes a novel DIA framework, called DIA-MTTP. The major novelty of the framework lies in that, while providing the DIA service in a PCS environment, it supports the use of third parties, but does not require full trust in the third parties. In achieving this property, a number of ideas also have been embedded in the design. These ideas include the use of multiple third parties and a hierarchical approach to their communication structure making the service more suited to resource-constrained user devices, the provision of two integrity assurance levels to balance the trade-off between security protection levels and the costs incurred, the application of a data deduplication measure to both new data and existing data updates to minimise the number of tags (re-)generated. In supporting the dynamic data and deduplication measure, a distributed data structure, called Multiple Mapping Tables (M2T), is proposed. Security analysis indicates that our framework is secure with the use of untrusted third parties. Performance evaluation indicates that our framework imposes less computational, communication and storage overheads than related works.
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