The effects of attention in auditory-visual integration revealed by time-varying networks.

Attention and audiovisual integration are crucial subjects in the field of brain information processing. A large number of previous studies have sought to determine the relationship between them through specific experiments, but failed to reach a unified conclusion. The reported studies explored the relationship through the frameworks of early, late, and parallel integration, though network analysis has been employed sparingly. In this study, we employed time-varying network analysis, which offers a comprehensive and dynamic insight into cognitive processing, to explore the relationship between attention and auditory-visual integration. The combination of high spatial resolution functional magnetic resonance imaging (fMRI) and high temporal resolution electroencephalography (EEG) was used. Firstly, a generalized linear model (GLM) was employed to find the task-related fMRI activations, which was selected as regions of interesting (ROIs) for nodes of time-varying network. Then the electrical activity of the auditory-visual cortex was estimated via the normalized minimum norm estimation (MNE) source localization method. Finally, the time-varying network was constructed using the adaptive directed transfer function (ADTF) technology. Notably, Task-related fMRI activations were mainly observed in the bilateral temporoparietal junction (TPJ), superior temporal gyrus (STG), primary visual and auditory areas. And the time-varying network analysis revealed that V1/A1↔STG occurred before TPJ↔STG. Therefore, the results supported the theory that auditory-visual integration occurred before attention, aligning with the early integration framework.

Bone age assessment based on deep neural networks with annotation-free cascaded critical bone region extraction.

Bone age assessment (BAA) from hand radiographs is crucial for diagnosing endocrinology disorders in adolescents and supplying therapeutic investigation. In practice, due to the conventional clinical assessment being a subjective estimation, the accuracy of BAA relies highly on the pediatrician's professionalism and experience. Recently, many deep learning methods have been proposed for the automatic estimation of bone age and had good results. However, these methods do not exploit sufficient discriminative information or require additional manual annotations of critical bone regions that are important biological identifiers in skeletal maturity, which may restrict the clinical application of these approaches. In this research, we propose a novel two-stage deep learning method for BAA without any manual region annotation, which consists of a cascaded critical bone region extraction network and a gender-assisted bone age estimation network. First, the cascaded critical bone region extraction network automatically and sequentially locates two discriminative bone regions via the visual heat maps. Second, in order to obtain an accurate BAA, the extracted critical bone regions are fed into the gender-assisted bone age estimation network. The results showed that the proposed method achieved a mean absolute error (MAE) of 5.45 months on the public dataset Radiological Society of North America (RSNA) and 3.34 months on our private dataset.

G3BP2 regulates oscillatory shear stress-induced endothelial dysfunction.

GTPase-activating SH3 domain-binding protein 2 (G3BP2) is a mediator that responds to environmental stresses through stress granule formation and is involved in the progression of chronic diseases. However, no studies have examined the contribution of G3BP2 in the oscillatory shear stress (OSS)-induced endothelial dysfunction. Here we assessed the effects of G3BP2 in endothelial cells (ECs) function and investigated the underlying mechanism. Using shear stress apparatus and partial ligation model, we identified that stress granule-related genes in ECs could be induced by OSS with RNA-seq, and then confirmed that G3BP2 was highly and specifically expressed in athero-susceptible endothelia in the OSS regions. G3bp2 -/- Apoe -/- mice had significantly decreased atherosclerotic lesions associated with deficiency of G3BP2 in protecting endothelial barrier function, decreasing monocyte adhesion to ECs and inhibiting the proinflammatory cytokine levels. Furthermore, loss of G3BP2 diminished OSS-induced inflammation in ECs by increasing YAP nucleocytoplasmic shuttling and phosphorylation. These data demonstrate that G3BP2 is a critical OSS regulated gene in regulating ECs function and that G3BP2 inhibition in ECs is a promising atheroprotective therapeutic strategy.

LncRNA OR2A1-AS1 index predicts survival in germinal center-like diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive form of non-Hodgkin lymphoma. Long noncoding RNA (lncRNA) has been evaluated as prognostic markers in various carcinomas. However, the prognostic value of the lncRNA index in DLBCL has not been fully understood. Hence, this study aimed to identify the prognostic value of lncRNA olfactory receptor family 2 subfamily A member 1-antisense RNA 1 (OR2A1-AS1) in DLBCL. METHODS: The Gene Expression Omnibus (GEO) database was used to obtain the GSE97336 dataset comprising lncRNA expression profiles. Quantitative reverse transcription polymerase chain reaction (QRT-PCR) was conducted to evaluate the expression of OR2A1-AS1 in 98 cases of DLBCL. RESULTS: OR2A1-AS1 expression was considerably reduced in DLBCL patients, reduced OR2A1-AS1 expression was linked to a shorter overall survival (OS) and progression-free survival (PFS) in DLBCL patients, especially those with the germinal center B-cell-like subtype (GCB). Multivariate analysis (MVA) revealed that the OR2A1-AS1 index had prognostic significance. Patients with low OR2A1-AS1 expression have a poor prognosis. CONCLUSIONS: OR2A1-AS may represent an effective predictor of patients' outcomes with DLBCL.

Temporal-spatial low shear stress induces heterogenous distribution of hematopoietic stem cell budding in zebrafish.

Hematopoietic stem/progenitor cells (HSPCs) originate from endothelial cells (ECs) localized on the ventral side of the dorsal aorta (DA), and hemodynamic parameters may suffer sharp changes in DA at HSPCs development stage for intersegmental vessel formation. However, the temporal-spatial shear stress parameters and biomechanics mechanisms of HSPC budding remain unknown. Here, we found that the hematopoietic endothelium (HE) in the aorta-gonad-mesonephros was heterogeneous; that is, HEs were mainly distributed at the ventral side of the vascular bifurcation in zebrafish embryos, which was found to show low shear stress (LSS) through numerical simulation analysis. Furthermore, HSPCs localized in the posterior somite of aorta-gonad-mesonephros with slow velocity. On the temporal scale, there was a slow velocity and LSS during HE budding from 36 h post-fertilization and decreased shear stress with drug expanded HSPC numbers. Mechanistically, matrix metalloproteinase (MMP) expression and macrophage chemotaxis were significantly increased in HEs by RNA-seq. After treatment with an MMP13 inhibitor, HSPCs were significantly reduced in both the aorta-gonad-mesonephros and caudal hematopoietic tissue in embryos. Our results show that HSPC budding is heterogeneous, and the mechanism is that physiological LSS controls the emergence of HSPCs by promoting the accumulation of macrophages and subsequent MMP expression.

The efficacy and safety of combined traditional Chinese and western medicine in the treatment of chronic obstructive pulmonary disease complicated with respiratory failure: a systematic review and meta-analysis study.

BACKGROUND: The conventional drugs to treat chronic obstructive pulmonary disease (COPD) complicated with respiratory failure (RF) (COPD + RF) in western medicine include antibiotics, etc., but the patients have serious adverse reactions and are prone to drug resistance. This study aims to analyze the curative effect of traditional Chinese medicine (TCM) combined with Western medicine (WM) in treating COPD + RF. METHODS: Randomized controlled studies on the treatment of COPD with RF were searched in PubMed, Web of Science, Embase, and The Cochrane Library. Outcome measures were treatment efficiency, oxygen partial pressure (PO2), partial pressure of carbon dioxide (PCO2), and pulmonary function [forced expiratory volume in 1 second (FEV1)%]. The Cochrane Reviewer's Handbook 4.2.5 was adopted for quality assessment of studies, and the data was analyzed using RevMan 5.3. RESULTS: Seven suitable articles were selected, including 490 patients. The literature quality met the requirements of this article, and there was no obvious publication bias. The effective rate of patients in the combined TCM and WM treatment group and control group (WM treatment) was analyzed as odds ratio (OR) [95% confidence interval (CI): 5.40 (3.14 to 9.29)], and statistically tested as Z=6.09 (P<0.00001). The analysis structure of PO2 after treatment was mean difference (MD) (95% CI): 5.92 (2.27 to 9.56), and the statistical analysis suggested Z=3.18, P=0.001. The analysis of PCO2 after treatment was MD (95% CI): -4.53 (-7.14 to -1.92), and Z=3.40, P=0.0007. The analysis structure of lung function index data was MD (95% CI): 8.16 (2.57 to 13.75), and Z=2.86 (P=0.004). DISCUSSION: The TCM combined with WM can effectively treat the symptoms related to COPD; the treatment efficiency is significantly improved compared with traditional WM; and the PO2, PCO2, and lung function (FEV1%) are improved for sure after treatment. Data of this study show that the combined treatment of TCM and WM has a good therapeutic effect on the acute exacerbation of COPD complicated with RF, which is worthy of clinical application. However, the included outcome indexes in this study were not sufficient, and the sample size and outcome indexes should be further expanded in the future.

M2 macrophage-derived exosomes promote the c-KIT phenotype of vascular smooth muscle cells during vascular tissue repair after intravascular stent implantation.

Rationale: For intravascular stent implantation to be successful, the processes of vascular tissue repair and therapy are considered to be critical. However, the mechanisms underlying the eventual fate of vascular smooth muscle cells (VSMCs) during vascular tissue repair remains elusive. In this study, we hypothesized that M2 macrophage-derived exosomes to mediate cell-to-cell crosstalk and induce dedifferentiation phenotypes in VSMCs. Methods:In vivo, 316L bare metal stents (BMS) were implanted from the left iliac artery into the abdominal aorta of 12-week-old male Sprague-Dawley (SD) rats for 7 and 28 days. Hematoxylin and eosin (HE) were used to stain the neointimal lesions. En-face immunofluorescence staining of smooth muscle 22 alpha (SM22α) and CD68 showed the rat aorta smooth muscle cells (RASMCs) and macrophages. Immunohistochemical staining of total galactose-specific lectin 3 (MAC-2) and total chitinase 3-like 3 (YM-1) showed the total macrophages and M2 macrophages. In vitro, exosomes derived from IL-4+IL-13-treated macrophages (M2Es) were isolated by ultracentrifugation and characterized based on their specific morphology. Ki-67 staining was conducted to assess the effects of the M2Es on the proliferation of RASMCs. An atomic force microscope (AFM) was used to detect the stiffness of the VSMCs. GW4869 was used to inhibit exosome release. RNA-seq was performed to determine the mRNA profiles of the RASMCs and M2Es-treated RASMCs. Quantitative real-time PCR (qRT-PCR) analysis was conducted to detect the expression levels of the mRNAs. Western blotting was used to detect the candidate protein expression levels. T-5224 was used to inhibit the DNA binding activity of AP-1 in RASMCs. Results: M2Es promote c-KIT expression and softening of nearby VSMCs, hence accelerating the vascular tissue repair process. VSMCs co-cultured in vitro with M2 macrophages presented an increased capacity for de-differentiation and softening, which was exosome dependent. In addition, the isolated M2Es helped to promote VSMC dedifferentiation and softening. Furthermore, the M2Es enhanced vascular tissue repair potency by upregulation of VSMCs c-KIT expression via activation of the c-Jun/activator protein 1 (AP-1) signaling pathway.Conclusions: The findings of this study emphasize the prominent role of M2Es during VSMC dedifferentiation and vascular tissue repair via activation of the c-Jun/AP-1 signaling pathway, which has a profound impact on the therapeutic strategies of coronary stenting techniques.

Lactic acid-mediated endothelial to mesenchymal transition through TGF-ß1 contributes to in-stent stenosis in poly-L-lactic acid stent.

Currently, bioresorbable stents made with biodegradable materials are attracting more and more attentions in cardiovascular tissue engineering. Especially, poly-L-lactic acid (PLLA) stent has been regarded as the most promising one due to excellent biodegradability until serious in-stent restenosis at late stage was reported. This imply that the PLLA stent has side effect in cell function, and it is rarely reported the effect of degradation product of PLLA on endothelial function. Here we reported that lactic acid (LA) not acidic pH induced endothelial-to-mesenchymal transition (EndMT) leading to vascular fibrosis which may contribute to in-stent stenosis after PLLA stent implantation. Furthermore, we found TGF-ß1 signaling was involved in boosting EndMT by LA. These results demonstrate a mechanism of in-stent stenosis induced by PLLA and indicate its utility for the future design of polymeric vascular scaffolds.

Overview of Crosstalk Between Multiple Factor of Transcytosis in Blood Brain Barrier.

Blood brain barrier (BBB) conserves unique regulatory system to maintain barrier tightness while allowing adequate transport between neurovascular units. This mechanism possess a challenge for drug delivery, while abnormality may result in pathogenesis. Communication between vascular and neural system is mediated through paracellular and transcellular (transcytosis) pathway. Transcytosis itself showed dependency with various components, focusing on caveolae-mediated. Among several factors, intense communication between endothelial cells, pericytes, and astrocytes is the key for a normal development. Regulatory signaling pathway such as VEGF, Notch, S1P, PDGFß, Ang/Tie, and TGF-ß showed interaction with the transcytosis steps. Recent discoveries showed exploration of various factors which has been proven to interact with one of the process of transcytosis, either endocytosis, endosomal rearrangement, or exocytosis. As well as providing a hypothetical regulatory pathway between each factors, specifically miRNA, mechanical stress, various cytokines, physicochemical, basement membrane and junctions remodeling, and crosstalk between developmental regulatory pathways. Finally, various hypotheses and probable crosstalk between each factors will be expressed, to point out relevant research application (Drug therapy design and BBB-on-a-chip) and unexplored terrain.

Responsiveness of voltage-gated calcium channels in SH-SY5Y human neuroblastoma cells on micropillar substrates.

In this study, poly-L-lactic acid micropillar substrates were fabricated to evaluate the influence of topographic substrates on cell morphological and functional characteristics, such as spreading area, voltage-gated calcium channels (VGCCs) and membrane potential. The proliferation, spreading area, perimeter and circularity of SH-SY5Y cells interfaced with different substrates were first investigated. In addition, the cytoskeleton and focal adhesion of a cell as important manifestations of cell morphology were analyzed by immunofluorescence. VGCC responsiveness was evaluated by measuring the dynamic changes in intracellular Ca2+ evoked by 50 mM extracellular K+. To determine study whether the differences in VGCC responsiveness were caused by the differences in VGCC gene expression, the expression of N/L- type VGCCs was determined by qPCR and fluorescence staining. Notably, improved measurement of the membrane potential with potentiometric fluorescent dye TMRM was applied to determine the membrane potential of SH-SY5Y cells. Results indicated that the SH-SY5Y cells were deformed significantly to adapt to the substrates; however, no distinct effect on the proliferative ability of SH-SY5Y cells was observed. The micropillar substrates markedly influenced VGCC responsiveness, which correlated strongly with cell spreading but not with VGCC expression. The resting membrane potential of SH-SY5Y cells cultured on different substrates also changed, but no effect on responsiveness of VGCC was observed. These results suggest that the effect of the micropillar substrates on cell VGCC responsiveness may be attributed to changes in the functionality of the ion channel itself. Thus, topographic substrates can be used to engineer cell functionality in cell-based drug screening.