The push−pull conjugated molecules 2,7-bis-(1H-pyrrol-2-yl)ethynyl-1,8-naphthyridine (BPN) and 2,7-bis(1H-indol-2-yl)ethynyl-1,8-naphthyridine (BIN) adopting daad relays of proton donors (d) and ...acceptors (a) form multiple hydrogen-bonding complexes with various monosaccharides that possess complementary adda sequences. Although the free BPN emits blue light at λmax = 475 nm in CH2Cl2, its complexation with octyl β-d-glucopyranoside gives green fluorescence at λmax = 535 nm. The excellent photophysical properties make BPN a highly sensitive probe for monitoring glucopyranoside to a detection limit of ∼100 pM. On the other hand, the CD-silent BIN molecule binds with monosaccharides to form the CD-active multiple hydrogen-bonding complexes, which exhibit the remarkable chirality dependent helicities consistent with the prediction by the ab initio approaches. On the basis of the similar daad cleft and hence the binding property, the fluorescence and CD absorption methods in BPN and BIN, respectively, are complementary, which, in combination with computational molecular modeling, not only give a detailed insight into the structures of the receptor-saccharide complexes in solution, but also differentiate octyl β-d-glucopyranoside from its enantiomer and other monosaccharides.
α‐1‐Antitrypsin (α1‐AT) deficiency is the most common cause of metabolic pediatric liver disease. Hepatocellular injury is caused by toxicity of the mutant α‐1‐antitrypsin Z (α1‐ATZ) molecule ...retained within hepatocytes. In these studies, we used the PiZ transgenic mouse model of α1‐AT deficiency to examine hepatocellular proliferation in response to chronic liver injury resulting from this metabolic disease. The results showed increased hepatocellular proliferation and caspase 9 activation in male PiZ mice compared with female PiZ and wild‐type mice. Hepatic α1‐AT mRNA and protein expression also were increased in male PiZ mice, suggesting that greater hepatocellular proliferation and caspase activation in males results from increased hepatotoxicity associated with greater intracellular α1‐ATZ accumulation. Testosterone treatment of female PiZ mice increased α1‐ATZ expression and hepatocellular proliferation to a level comparable with that in males. In PiZ mice, hepatocytes devoid of intracellular α1‐AT globules had a proliferative advantage compared with globule‐containing hepatocytes. However, this advantage is relative because both globule‐containing and globule‐devoid hepatocytes exhibited comparable proliferation after partial hepatectomy. In conclusion, these data indicate that intracellular retention of mutant α1‐ATZ is associated with a regenerative stimulus leading to increased hepatocellular proliferation, that gender‐specific signals influence the degree of α1‐AT expression and associated hepatic injury, and that hepatocytes devoid of α1‐ATZ have a proliferative advantage over cells that accumulate the mutant protein. This selective proliferation suggests that hepatocellular transplantation may be applicable for treatment of this and other slowly progressive metabolic liver diseases (HEPATOLOGY 2004;39:1048–1055.)
A newly developed method, NNPCA, integrates two data driven techniques, neural network (NN) and principal component analysis (PCA), for process monitoring. NN is used to summarize the operating ...process information into a nonlinear dynamic mathematical model. Chemical dynamic processes are so complex that they are presently ahead of theoretical methods from a fundamental physical standpoint. NN functions as the nonlinear dynamic operator to remove processes' nonlinear and dynamic characteristics. PCA is employed to generate simple monitoring charts based on the multivariable residuals derived from the difference between the process measurements and the neural network prediction. It can evaluate the current performance of the process. Examples from the recent monitoring practice in the industry and the large-scale system in the Tennessee Eastman process problem are presented to help the reader delve into the matter.
To investigate the effect of non-breathing-related sleep fragmentation on cognitive function in patients with atherosclerotic cerebral small vessel disease(CSVD).
Seventy-two patients with ...arteriosclerotic CSVD in the Department of Neurology, the Third Affiliated Hospital of Sun Yat-sen University were enrolled in this study from August 2017 to July 2018. The patients undertook MRA(Magnetic Resonance Angiography)+SWI(Susceptibility weighted imaging), polysomnography, Montreal Cognitive Inventory (MoCA) and Concise Mental State Examination (MMSE). The patients were divided into study group (≥19) and control group (<19) according to the median number of arousal events (median
19) at night.
The sleep efficiency, rapid eye movement (REM) sleep ratio and non-rapid eye movement-3 (NREM-3) sleep ratio of the study group were significantly lower than those of the control group (
0.05), and the total MoCA score (18.2±4.3) , visual space score(1.9±1.4) and delayed recall score(1.4±0.9) of the study group were significa
Our study previously showed that estrogen and progesterone stimulated the production of matrix metalloproteinase-14 MMP-14, or also named membrane type matrix metalloproteinses-1 (MT1-MMP) in ...osteoblastic cells. MMP-14 was implied to regulate the function of osteoblasts by degrading bone matrix or growth factors, but the mechanism is unclear. Since MMP-14 plays a role primarily through the catalytic domain, and truncated MMP-14 containing the catalytic domain and lacking transmembrane domain can be secreted into medium by cultured cells, our present study was performed to observe the direct effects of recombinant MMP-14 catalytic domain on cultured human osteoblastic osteogenic sarcoma (SaOS)-2 cells. Our data showed that recombinant MMP-14 catalytic domain activated proMMP-2 secreted into media by SaOS-2 cells, and this process was blocked by ethylenediamine tetraacetic acid (EDTA) treatment. Recombinant MMP-14 catalytic domain inhibited the adhesion of SaOS-2 cells to immobilized type I collagen or fibronectin in a dose-dependent manner, and these effects on SaOS-2 cells were abolished by EDTA. Recombinant MMP-14 catalytic domain induced SaOS-2 cells apoptosis in a dose-dependent manner, and apoptosis-inducing activity of MMP-14 catalytic domain was blocked if it was treated with EDTA. In conclusion, we revealed that recombinant MMP-14 catalytic domain induced SaOS-2 cells apoptosis. We also indirectly showed the activity of MMP-14 catalytic domain to degrade extracellular matrix (ECM) in cultures of SaOS-2 cells through Gelatin Zymograms and adhesion assay. This suggests that since adhesion of cells to ECM serves as a survival mechanism in osteoblasts, the catalytic activity of recombinant MMP-14 catalytic domain on matrix proteins contributes to its apoptosis-inducing activity.
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Phenolic groups are responsible for the high clearance and low oral bioavailability of the estrogen receptor alpha (ERα) clinical candidate GDC-0927. An exhaustive search for a backup ...molecule with improved pharmacokinetic (PK) properties identified several metabolically stable analogs, although in general at the expense of the desired potency and degradation efficiency. C-8 hydroxychromene 30 is the first example of a phenol-containing chromene that not only maintained excellent potency but also exhibited 10-fold higher oral exposure in rats. The improved in vivo clearance in rat was hypothesized to be the result of C-8 hydroxy group being sterically protected from glucuronide conjugation. The excellent potency underscores the possibility of replacing the presumed indispensable phenolic group at C-6 or C-7 of the chromene core. Co-crystal structures were obtained to highlight the change in key interactions and rationalize the retained potency.
Abstract Myocardial reperfusion injury is increasingly recognized as an inflammatory process, characterized by neutrophil recruitment and subsequently excessive release of pro-inflammatory factors. ...Recently, the extracellular cyclophilin A (CypA) has been showed to play an important role in initiation and development of inflammation by chemo trafficking of leukocytes into inflamed tissues, eliciting massive release of pro-inflammatory cytokines, and inducing production of matrix metalloproteinases. Also, the agents targeting CypA have been demonstrated to promise anti-inflammatory effects in the different experimental models of inflammatory diseases including acute lung injury, rheumatoid arthritis, and atherosclerosis. Therefore, we hypothesize that the extracellular CypA may in some way implicated in the pathogenesis of reperfusion-induced inflammatory process, and the specific inhibitors of the extracellular CypA can provide a protection against the myocardial reperfusion injury.
Cystoscopy enables the visualisation of suspicious bladder lesions but lacks the ability to provide real-time histopathologic information. Confocal laser endomicroscopy (CLE) is a probe-based optical ...technique that can provide real-time microscopic images. This high-resolution optical imaging technique may enable real-time tumour grading during cystoscopy.
To validate and adapt CLE criteria for bladder cancer diagnosis and grading.
Prospectively, 73 patients scheduled for transurethral resection of bladder tumour(s) were included. CLE imaging was performed intraoperatively prior to en bloc resection. Histopathology was the reference standard for comparison.
Cystoscopic CLE imaging.
Three independent observers evaluated the CLE images to classify tumours as low- or high-grade urothelial carcinoma (UC), or benign lesions. Interobserver agreement was calculated with Fleiss kappa analysis and diagnostic accuracy with 2×2 tables.
Histopathology of 66 lesions (53 patients) revealed 25 low-grade UCs, 27 high-grade UCs, and 14 benign lesions. For low-grade UC, most common features were papillary configuration (100%), distinct cell borders (81%), presence of fibrovascular stalks (79%), cohesiveness of cells (77%), organised cell pattern (76%), and monomorphic cells (67%). A concordance between CLE-based classification and histopathology was found in 19 cases (76%). For high-grade UC, pleomorphic cells (77%), indistinct cell borders (77%), papillary configuration (67%), and disorganised cell pattern (60%) were the most common features. A concordance with histopathology was found in 19 cases (70%). In benign lesions, the most prevalent features were disorganised cell pattern (57%) and pleomorphic cells (52%), and a concordance with histopathology was found in four cases (29%).
The CLE criteria enable identification of UC. CLE features correlate to histopathologic features that may enable real-time tumour grading. However, flat lesions remain difficult to classify.
Confocal laser endomicroscopy may enable real-time cancer differentiation during cystoscopy, which is important for prognosis and disease management.
The feasibility of inverse modeling a multicomponent, size‐resolved aerosol evolving by condensation/evaporation is investigated. The adjoint method is applied to the multicomponent aerosol dynamic ...equation in a box model (zero‐dimensional) framework. Both continuous and discrete formulations of the model (the forward equation) and the adjoint are considered. A test example is studied in which the initial aerosol size composition distribution and the pure component vapor concentrations (i.e., vapor pressures) are estimated on the basis of measurements of all species, or a subset of the species, and the entire size distribution, or a portion of the size distribution. It is found that the adjoint method can successfully retrieve the initial size distribution and the pure component vapor concentrations even when only a subset of the species or a portion of the size distribution is observed, although this success is shown to depend upon the form of the initial estimates, the nature of the observations, and the length of the assimilation period. The results presented here provide a basis for the inverse modeling of aerosols in three‐dimensional atmospheric chemical transport models.
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