Alzheimer's disease (AD) is the most common form of dementia in the elderly and represents an important and increasing clinical challenge in terms of diagnosis and treatment. Mutations in the genes ...encoding amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) are responsible for early-onset autosomal dominant AD. The ε4 allele of the apolipoprotein E (APOE) gene has been recognized as a major genetic risk factor for the more common, complex, late-onset AD. Fibrillar deposits by phosphorylated tau are also a key pathological feature of AD. The retromer complex also has been reported to late-onset AD. More recently, genome-wide association studies (GWASs) identified putative novel candidate genes associated with late-onset AD. Lastly, several studies showed that circulating microRNAs (miRNAs) in the cerebrospinal fluid (CSF) and blood serum of AD patients can be used as biomarkers in AD diagnosis. This review addresses the advances and challenges in determining genetic and diagnostic markers for complex AD pathogenesis.
•Various mutations of APP, PSEN1, and PSEN2 have been reported in AD pathogenesis.•Diverse mutations of APOE and tau gene are also associated with AD.•Dysfunction of retromer would accelerate APP processing, causing late-onset AD.•Many GWASs have identified genetic markers including SNPs, related to AD.•Circulating miRNAs in the CSF and blood serum have been found as biomarkers in AD.
The effect of hydrogen (H) charging on the nanoindentation response of a selective laser melted (SLM) 316L austenitic stainless steel was investigated and compared with its conventionally ...manufactured (CM) counterpart. Results show that the hardness increment in the SLM samples due to H charging is relatively smaller. Thermal desorption spectroscopy analysis suggests that the charged SLM alloy has not only a smaller H content but a lower apparent H diffusivity in comparison to the CM alloy. This was attributed to the ultrafine solidification cell structure in the SLM alloy. Through the low-load nanoindentation experiments and forward-scattered electron imaging analysis, statistical distributions of the hardness of the cell walls and interiors were assessed. The cell walls, consisting of high-density dislocations with segregated elements, were relatively insensitive to H charging than the cell interiors. These results are discussed in terms of the apparent H solubility and diffusivity in the SLM alloy.
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The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance have been explored in both animal and human studies. However, our current ...understanding of obesity-associated insulin resistance relies on studies of artificial metabolic extremes. The purpose of this study was to explore the roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in human patients with modest obesity and early metabolic dysfunction. We obtained omental adipose tissue and fasting blood samples from 51 females undergoing gynecologic surgery. We investigated serum concentrations of proinflammatory cytokines and adipokines as well as the mRNA expression of proinflammatory and macrophage phenotype markers in visceral adipose tissue using ELISA and quantitative RT-PCR. We measured adipose tissue inflammation and macrophage infiltration using immunohistochemical analysis. Serum levels of adiponectin and leptin were significantly correlated with HOMA-IR and body mass index. The levels of expression of MCP-1 and TNF-α in visceral adipose tissue were also higher in the obese group (body mass index ≥ 25). The expression of mRNA MCP-1 in visceral adipose tissue was positively correlated with body mass index (r = 0.428, p = 0.037) but not with HOMA-IR, whereas TNF-α in visceral adipose tissue was correlated with HOMA-IR (r = 0.462, p = 0.035) but not with body mass index. There was no obvious change in macrophage phenotype or macrophage infiltration in patients with modest obesity or early metabolic dysfunction. Expression of mRNA CD163/CD68 was significantly related to mitochondrial-associated genes and serum inflammatory cytokine levels of resistin and leptin. These results suggest that changes in the production of inflammatory biomolecules precede increased immune cell infiltration and induction of a macrophage phenotype switch in visceral adipose tissue. Furthermore, serum resistin and leptin have specific roles in the regulation of adipose tissue macrophages in patients with modest obesity or early metabolic dysfunction.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Retroviral vectors show long‐term gene expression in gene therapy through the integration of transgenes into the human cell genome. Murine leukemia virus (MLV), a well‐studied gammaretrovirus, has ...been often used as a representative retroviral vector. However, frequent integrations of MLV‐based vectors into transcriptional start sites (TSSs) could lead to the activation of oncogenes by enhancer effects of the genetic components within the vectors. Therefore, the MLV integration preference for TSSs limits its wider use in clinical applications. To reduce the integration preference of MLV‐based vectors, we attempted to perturb the structure of the viral integrase that plays a key role in determining integration sites. For this goal, we inserted histones and leucine zippers, having DNA‐binding property, into internal sites of MLV integrase. This integrase engineering yielded multiple mutant vectors that showed significantly different integration patterns compared with that of wild‐type vector. Some mutant vectors did not prefer the key regulatory genomic domains of human cells, TSSs. Moreover, a couple of engineered vectors did not integrate into the genomic sites near the TSSs of oncogenes. Overall, this study suggests that structural perturbation of integrase is a simple way to develop safer MLV‐based retroviral vectors for use in clinical applications.
Frequent integrations of murine leukemia virus (MLV) vector into regulatory regions of the human genome may cause the transformation of cells to cancerous ones, thereby limiting its wider use in clinical applications. Yang and coworkers developed new MLV‐based vectors by inserting histones and leucine zippers into the viral integrase. The engineered vectors did not prefer regulatory regions of the human genome during integration. The improved safety of the vectors would link to structural perturbation of the viral integrase, which was caused by the protein insertion.
Cholangiocarcinoma, the second most common hepatobiliary malignancy after hepatocellular carcinoma, is a heterogeneous disease entity with widely varying radiologic features, clinical behavior, and ...treatment approaches. In the detection, characterization, staging, and resectability assessment of cholangiocarcinoma, imaging studies are indispensable. Herein, an overview of the state-of-the-art imaging techniques is presented for the evaluation of intrahepatic and perihilar cholangiocarcinoma, as well as complementary multimodality and multiparametric imaging approaches for a more comprehensive evaluation. In addition, classification systems, new pathologic concepts in cholangiocarcinogenesis and premalignant lesions, and current trends in treatment approaches, which are vital to the imaging interpretation of cholangiocarcinoma, will be discussed.
RSNA, 2018.
Reactive oxygen species (ROS) contribute to the development of non-alcoholic fatty liver disease. ROS generation by infiltrating macrophages involves multiple mechanisms, including Toll-like receptor ...4 (TLR4)-mediated NADPH oxidase (NOX) activation. Here, we show that palmitate-stimulated CD11b
F4/80
hepatic infiltrating macrophages, but not CD11b
F4/80
Kupffer cells, generate ROS via dynamin-mediated endocytosis of TLR4 and NOX2, independently from MyD88 and TRIF. We demonstrate that differently from LPS-mediated dimerization of the TLR4-MD2 complex, palmitate binds a monomeric TLR4-MD2 complex that triggers endocytosis, ROS generation and increases pro-interleukin-1β expression in macrophages. Palmitate-induced ROS generation in human CD68
CD14
macrophages is strongly suppressed by inhibition of dynamin. Furthermore, Nox2-deficient mice are protected against high-fat diet-induced hepatic steatosis and insulin resistance. Therefore, endocytosis of TLR4 and NOX2 into macrophages might be a novel therapeutic target for non-alcoholic fatty liver disease.
Computed tomography (CT) and magnetic resonance (MR) imaging play critical roles in the diagnosis and staging of hepatocellular carcinoma (HCC). The second article of this two-part review discusses ...basic concepts of diagnosis and staging, reviews the diagnostic performance of CT and MR imaging with extracellular contrast agents and of MR imaging with hepatobiliary contrast agents, and examines in depth the major and ancillary imaging features used in the diagnosis and characterization of HCC.
The effect of porous structures on the electrocatalytic activity of N-doped carbon is studied by using electrochemical analysis techniques and the result is applied to synthesize highly active and ...stable Fe–N–C catalyst for oxygen reduction reaction (ORR). We developed synthetic procedures to prepare three types of N-doped carbon model catalysts that are designed for systematic comparison of the porous structures. The difference in their catalytic activity is investigated in relation to the surface area and the electrochemical parameters. We found that macro- and mesoporous structures contribute to different stages of the reaction kinetics. The catalytic activity is further enhanced by loading the optimized amount of Fe to prepare Fe–N–C catalyst. In both N-doped carbon and Fe–N–C catalysts, the hierarchical porous structure improved electrocatalytic performance in acidic and alkaline media. The optimized catalyst exhibits one of the best ORR performance in alkaline medium with excellent long-term stability in anion exchange membrane fuel cell and accelerated durability test. Our study establishes a basis for rationale design of the porous carbon structure for electrocatalytic applications.
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