Abstract The vascular grafts prepared by electrospinning often have relatively small pores, which limit cell infiltration into the grafts and hinder the regeneration and remodeling of the grafts into ...neoarteries. To overcome this problem, macroporous electrospun polycaprolactone (PCL) scaffolds with thicker fibers (5–6 μm) and larger pores (∼30 μm) were fabricated in the present study. In vitro cell culture indicated that macrophages cultured on thicker-fiber scaffolds tended to polarize into the immunomodulatory and tissue remodeling (M2) phenotype, while those cultured on thinner-fiber scaffolds expressed proinflammatory (M1) phenotype. In vivo implantation by replacing rat abdominal aorta was performed and followed up for 7, 14, 28 and 100 d. The results demonstrated that the macroporous grafts markedly enhanced cell infiltration and extracellular matrix (ECM) secretion. All grafts showed satisfactory patency for up to 100 days. At day 100, the endothelium coverage was complete, and the regenerated smooth muscle layer was correctly organized with abundant ECM similar to those in the native arteries. More importantly, the regenerated arteries demonstrated contractile response to adrenaline and acetylcholine-induced relaxation. Analysis of the cellularization process revealed that the thicker-fiber scaffolds induced a large number of M2 macrophages to infiltrate into the graft wall. These macrophages further promoted cellular infiltration and vascularization. In conclusion, the present study confirmed that the scaffold structure can regulate macrophage phenotype. Our thicker-fiber electrospun PCL vascular grafts could enhance the vascular regeneration and remodeling process by mediating macrophage polarization into M2 phenotype, suggesting that our constructs may be a promising cell-free vascular graft candidate and are worthy for further in vivo evaluation.
Major depressive disorder (MDD) is common and disabling, but its neuropathophysiology remains unclear. Most studies of functional brain networks in MDD have had limited statistical power and data ...analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. Twenty-five research groups in China established the REST-meta-MDD Consortium by contributing R-fMRI data from 1,300 patients with MDD and 1,128 normal controls (NCs). Data were preprocessed locally with a standardized protocol before aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to be increased in MDD. Instead, we found decreased DMN FC when we compared 848 patients with MDD to 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naïve MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDD. Exploratory analyses also revealed alterations in FC of visual, sensory-motor, and dorsal attention networks in MDD. We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates response to treatment. All R-fMRI indices of data contributed by the REST-meta-MDD consortium are being shared publicly via the R-fMRI Maps Project.
Land plants directly contact soil through their roots. An enormous diversity of microbes dwelling in root-associated zones, including endosphere (inside root), rhizoplane (root surface) and ...rhizosphere (soil surrounding the root surface), play essential roles in ecosystem functioning and plant health. Rice is a staple food that feeds over 50% of the global population. Its root is a unique niche, which is often characterized by an oxic region (e.g. the rhizosphere) surrounded by anoxic bulk soil. This oxic-anoxic interface has been recognized as a pronounced hotspot that supports dynamic biogeochemical cycles mediated by various functional microbial groups. Considering the significance of rice production upon global food security and the methane budget, novel insights into how the overall microbial community (i.e. the microbiome) of the rice root system influences ecosystem functioning is the key to improving crop health and sustainable productivity of paddy ecosystems, and alleviating methane emissions. This mini-review summarizes the current understanding of microbial diversity of rice root-associated compartments to some extent, especially the rhizosphere, and makes a comparison of rhizosphere microbial community structures between rice and other crops/plants. Moreover, this paper describes the interactions between root-related microbiomes and rice plants, and further discusses the key factors shaping the rice root-related microbiomes.
Epidemiological, preclinical and cellular studies in the last 5 years have shown that metformin exerts anti‐tumoral properties, but its mode of action in cancer remains unclear. Here, we investigated ...the effects of metformin on a mouse hepatocellular carcinoma (HCC) model and tumor‐associated T cell immune responses. Oral metformin administration led to a significant reduction of tumor growth, which was accompanied by decreased interleukin‐22 (IL‐22). Meanwhile, IL‐22‐induced STAT3 phosphorylation and upregulation of downstream genes Bcl‐2 and cyclin D1 were inhibited by metformin. At the cellular level, metformin attenuated Th1‐ and Th17‐derived IL‐22 production. Furthermore, metformin inhibited de novo generation of Th1 and Th17 cells from naive CD4+ cells. These observations were further supported by the fact that metformin treatment inhibited CD3/CD28‐induced IFN‐γ and IL‐17A expression along with the transcription factors that drive their expression (T‐bet Th1 and ROR‐γt Th17, respectively). The effects of metformin on T cell differentiation were mediated by downregulated STAT3 and STAT4 phosphorylation via the AMP‐activated kinase‐mammalian target of rapamycin complex 1 pathway. Notably, metformin led to a reduction in glucose transporter Glut1 expression, resulting in less glucose uptake, which is critical to regulate CD4+ T cell fate. Taken together, these findings provide evidence for the growth‐inhibitory and immune‐modulatory effects of metformin in HCC and thus, broaden our understanding about the action of metformin in liver cancer treatment.
What's new?
Over the last decade, metformin, an anti‐diabetic drug, has gained significant attention as an anti‐cancer drug because of its association with a dramatically decreased risk of some cancers. The underlying mechanisms of action, however, remain largely unknown. Here, using a mouse hepatocellular carcinoma (HCC) model, the authors found an important and previously unidentified effect of metformin with the inhibition of HCC growth through an indirect path mediated by IL‐22. The findings also provide evidence for immune‐modulatory effects of metformin in HCC. Taken together, these data broaden our current understanding of the mechanisms of action of metformin in liver cancer treatment.
Potassium ion channels are emerging as promalignant factors involved in cancer progression. In this study, we found that invading human gastric cancer cells express high levels of inwardly rectifying ...potassium channel 2.1 (Kir2.1). Silencing Kir2.1 markedly reduced the invasive and metastatic capabilities as well as the epithelial-mesenchymal transition (EMT) of gastric cancer cells. The promalignant nature of Kir2.1 in gastric cancer cells was independent of potassium permeation but relied on its interaction with serine/threonine-protein kinase 38 (Stk38) to inhibit ubiquitination and degradation of mitogen-activated protein kinase kinase kinase 2 (MEKK2). Degradation of MEKK2 was mediated by small mothers against decapentaplegic-specific E3 ubiquitin protein ligase 1 (Smurf1), which resulted in activation of the MEK1/2-ERK1/2-Snail pathway in gastric cancer cells. In human gastric cancer tissues, expression was high and positively correlated with invasion depth and metastatic status of the tumors as well as poor overall patient survival. Cox regression analysis identified Kir2.1 as an independent prognostic indicator for patients with gastric cancer. Our results suggest that Kir2.1 is an important regulator of gastric cancer malignancy and acts as a novel prognostic marker and a therapeutic target for gastric cancer.
Kir2.1 contributes to invasion and metastasis by a noncanonical ion permeation-independent signaling pathway and may act as a novel prognostic marker and therapeutic target for gastric cancer.
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Aberrant topological organization of whole-brain networks has been inconsistently reported in studies of patients with major depressive disorder (MDD), reflecting limited sample sizes. To address ...this issue, we utilized a big data sample of MDD patients from the REST-meta-MDD Project, including 821 MDD patients and 765 normal controls (NCs) from 16 sites. Using the Dosenbach 160 node atlas, we examined whole-brain functional networks and extracted topological features (e.g., global and local efficiency, nodal efficiency, and degree) using graph theory-based methods. Linear mixed-effect models were used for group comparisons to control for site variability; robustness of results was confirmed (e.g., multiple topological parameters, different node definitions, and several head motion control strategies were applied). We found decreased global and local efficiency in patients with MDD compared to NCs. At the nodal level, patients with MDD were characterized by decreased nodal degrees in the somatomotor network (SMN), dorsal attention network (DAN) and visual network (VN) and decreased nodal efficiency in the default mode network (DMN), SMN, DAN, and VN. These topological differences were mostly driven by recurrent MDD patients, rather than first-episode drug naive (FEDN) patients with MDD. In this highly powered multisite study, we observed disrupted topological architecture of functional brain networks in MDD, suggesting both locally and globally decreased efficiency in brain networks.
TM6SF2, predominantly expressed in the liver and intestine, is closely associated with lipid metabolism. We have demonstrated the presence of TM6SF2 in VSMCs within human atherosclerotic plaques. ...Subsequent functional studies were conducted to investigate its role in lipid uptake and accumulation in human vascular smooth muscle cells (HAVSMCs) using siRNA knockdown and overexpression techniques. Our results showed that TM6SF2 reduced lipid accumulation in oxLDL-stimulated VSMCs, likely through the regulation of lectin-like oxLDL receptor 1 (LOX-1) and scavenger receptor cluster of differentiation 36 (CD36) expression. We concluded that TM6SF2 plays a role in HAVSMC lipid metabolism with opposing effects on cellular lipid droplet content by downregulation of LOX-1 and CD36 expression.
•TM6SF2 is highly expressed in SMCs in intimal lesions of human coronary artery atheromas.•OxLDL upregulates the expression of TM6SF2 in a concentration- and time-dependent manner in HAVSMCs.•Knockdown of TM6SF2 enhances oxLDL uptake in HAVSMCs by upregulating the expression of LOX-1 and CD36.
PCSK9 (proprotein convertase subtilisin/kexin type 9) plays a critical role in cholesterol metabolism via the PCSK9-LDLR (low-density lipoprotein receptor) axis in the liver; however, evidence ...indicates that PCSK9 directly contributes to the pathogenesis of various diseases through mechanisms independent of its LDL-cholesterol regulation. The objective of this study was to determine how PCSK9 directly acts on vascular smooth muscle cells (SMCs), contributing to degenerative vascular disease. Approach and Results: We first examined the effects of PCSK9 on cultured human aortic SMCs. Overexpression of PCSK9 downregulated the expression of ApoER2 (apolipoprotein E receptor 2), a known target of PCSK9. Treatment with soluble recombinant human ApoER2 or the DNA synthesis inhibitor, hydroxyurea, inhibited PCSK9-induced polyploidization and other cellular responses of human SMCs. Treatment with antibodies against ApoER2 resulted in similar effects to those observed with PCSK9 overexpression. Inducible, SMC-specific knockout of
accelerated neointima formation in mouse carotid arteries and reduced age-related arterial stiffness. PCSK9 was expressed in SMCs of human atherosclerotic lesions and abundant in the "shoulder" regions of vulnerable atherosclerotic plaques. PCSK9 was also expressed in SMCs of abdominal aortic aneurysm, which was inversely related to the expression of smooth muscle α-actin.
Our findings demonstrate that PCSK9 inhibits proliferation and induces polyploidization, senescence, and apoptosis, which may be relevant to various degenerative vascular diseases.
Though several epidemiological surveys of psychiatric disorders have been carried out in China, only a few of them are concerned about the prevalence of psychiatric disorders in central Hunan and ...reveal the distribution of common psychiatric disorders and their comorbidities.
Achenbach's Child Behavior Checklist (CBCL), the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID), and Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) were administered to a stratified sample of 17,071 participants aged 6 to 16 years old from two cities in the central part of Hunan province. Twelve-month prevalence rates were calculated.
Twelve-month prevalence of the population was 9.74%. The most common psychiatric disorders were attention deficit hyperactivity disorder (ADHD) (4.96%), oppositional defiant disorder (ODD) (2.98%) and generalized anxiety disorder (GAD) (1.77%). Of those with a 12-month prevalence diagnosis, 34.6% had one or more comorbid psychiatric disorders. Most notably, ADHD had comorbidity rates of 25.15% with ODD, 18.18% with CD, 6.38% with GAD, and 3.66% with MDD.
Psychiatric disorders are common in Chinese children and adolescents. Being the most prevalent mental disorder, ADHD requires continued focus and support in awareness and education.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Plasticity of spine morphology is a universal phenomenon in rotifers. Some Brachionus calyciflorus clones consistently develop two posterolateral spines (PS) with similar length (Type A), but others ...(Type B) not. The underlying mechanisms remain unknown. In the present study, the resting eggs were collected from the same B. calyciflorus strain, their hatchlings (stem rotifers) were categorized into types A and B, and then, clonally cultured for eight generations at different algal densities or temperatures. The results showed that the PS varied in length among different temperatures and food levels, but inherent differences between types A and B were always observed, indicating that differentiation between types A and B might not associate with temperature or food availability. Next, we compared the population growth and PS length between types A and B at the general condition (control), in responses to Asplanchna kairomone, Keratella tropica and Moina macrocopa. The results showed that type B had higher population growth rate than type A, suggesting the higher adaptability of type B in the general condition. In response to Asplanchna kairomone, the PS length of both types A and B was significantly induced, and their PS length was similar, but type B showed higher population growth rate than type A. Coculture with M. macrocopa significantly lengthened the PS of type B but not type A, and types A and B showed similar population growth curves. Coculture with K. tropica did not affect significantly the PS length of types A and B. However, type A showed significantly and greatly higher population density and population growth rate than type B, indicating a much stronger competition ability of type A than type B against K. tropica. Overall, these results indicated that consistent development of PS might facilitate B. calyciflorus to defend against small competitors.
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