Current anti-AIDS therapeutic agents and treatment regimens can provide a dramatically improved quality of life for HIV-positive
people, many of whom have no detectable viral load for prolonged periods of time. Despite this, curing AIDS remains an elusive
goal, partially due to the occurrence of drug resistance. Since the development of resistance is linked to, among other things,
fluctuating drug levels, our long-term goal has been to develop nanotechnology-based drug delivery systems that can improve
therapy by more precisely controlling drug concentrations in target cells. The theme of the current study is to investigate
the value of combining AIDS drugs and modifiers of cellular uptake into macromolecular conjugates having novel pharmacological
properties. 相似文献
Functional magnetic resonance imaging (fMRI) in resting state can be used to evaluate the functional organization of the human brain in the absence of any task or stimulus. The functional connectivity (FC) has non-stationary nature and consented to be varying over time. By considering the dynamic characteristics of the FC and using graph theoretical analysis and a machine learning approach, we aim to identify the laterality in cases of temporal lobe epilepsy (TLE).
Methods
Six global graph measures are extracted from static and dynamic functional connectivity matrices using fMRI data of 35 unilateral TLE subjects. Alterations in the time trend of the graph measures are quantified. The random forest (RF) method is used for the determination of feature importance and selection of dynamic graph features including mean, variance, skewness, kurtosis, and Shannon entropy. The selected features are used in the support vector machine (SVM) classifier to identify the left and right epileptogenic sides in patients with TLE.
Results
Our results for the performance of SVM demonstrate that the utility of dynamic features improves the classification outcome in terms of accuracy (88.5% for dynamic features compared with 82% for static features). Selecting the best dynamic features also elevates the accuracy to 91.5%.
Conclusion
Accounting for the non-stationary characteristics of functional connectivity, dynamic connectivity analysis of graph measures along with machine learning approach can identify the temporal trend of some specific network features. These network features may be used as potential imaging markers in determining the epileptogenic hemisphere in patients with TLE.
Penetration of epithelial cells represents the rate-determining step for the absorption of many drugs and pharmaceutical macromolecules such as proteins and nucleic acid therapeutics. While the potential of using cell-penetrating peptides (CPPs) to facilitate absorption has been increasingly recognized, the mechanism of cell penetration and the uptake into certain cells have recently been called into question due to methodological artifacts. Therefore, the objective of this study was to quantitatively assess the ability of RI-Tat-9, a proteolytically stable CPP, to penetrate epithelial cell monolayers. The permeability of RI-Tat-9 with two epithelial cell lines, Madin-Darby canine kidney (MDCK) and Caco-2 cells, was comparable to the leakiness of the respective intact monolayers. Microscopic imaging showed that fluorescence-tagged RI-Tat-9 did not enter these cells, further supporting a paracellular transport mechanism. Although insufficient data were generated in these studies to generalize the observed phenomenon, the entry of RI-Tat-9 into nonepithelial T lymphocytic MT2 cells, possibly by endocytosis, suggested that a cell type-specific barrier might exist that controlled uptake of RI-Tat-9 by cells. Compared to that in MT2 and HeLa cells, the active uptake of the peptide into MDCK monolayers was much slower and showed no dependence of cell energy. Furthermore, the equilibrium binding of RI-Tat-9 to MDCK cells at 0 degrees C was indicative of an interaction with a nonspecific receptor. A correlation between binding density and concentration difference across a leaky separation barrier suggested that repulsion of free peptide molecules by bound peptide molecules at the MDCK monolayer surface may be significant at micromolar concentrations. The results of this study quantitatively show that Tat CPP uptake into two commonly used epithelial cell types is minimal and possibly cell type-specific. Implications for Tat CPP-assisted drug delivery are discussed. 相似文献
Purpose. To investigate the potential for delivering large peptides orally by altering their absorptive transport pathways and improving intestinal permeability. The absorptive transport of retro-inverso (R.I.-) K-Tat9 and R.I.-K(biotin)-Tat9, novel peptidic inhibitors of the Tat protein of HIV-1, and their interactions with human SMVT (hSMVT), a high affinity, low capacity transporter, were investigated using Caco-2 and transfected CHO cells.
Methods. Following synthesis on a PAL resin using Fmoc chemistry, the transport of R.I.-K-Tat9 (0.01-25 M) and R.I.-K(biotin)-Tat9 (0.1-25 M) was evaluated across Caco-2 cells. The transport and kinetics of biotin, biocytin and desthiobiotin (positive controls for SMVT) were also determined. Uptake of R.I.-K-Tat9 and R.I.-K(biotin)-Tat9 (both 0.1-10 M) was determined in CHO/hSMVT and CHO/pSPORT (control) cells.
Results. The absorptive transport of R.I.-K-Tat9 was passive, low (Pm1 × 10–6 cm/sec) and not concentration dependent. R.I.-K(biotin)-Tat9 permeability was 3.2-fold higher than R.I.-K-Tat9 demonstrating active (Ea = 9.1 kcal/mole), concentration dependent and saturable transport (Km = 3.3 M). R.I.-K(biotin)-Tat9 uptake in CHO/hSMVT cells (Km = 1.0 M) was 500-fold greater than R.I.-K-Tat9 (at 10 M). R.I.-K(biotin)-Tat9 transport in Caco-2 and CHO/hSMVT cells was significantly inhibited by known substrates of SMVT including biotin, biocytin, and desthiobiotin. Passive uptake of R.I.-K(biotin)-Tat9 was significantly greater than R.I.-K-Tat9 uptake in CHO/pSPORT cells.
Conclusions. These results demonstrate that the structural modification of R.I.-K-Tat9 to R.I.-K(biotin)-Tat9 altered its intestinal transport pathway resulting in a significant improvement in its absorptive permeability by enhancing nonspecific passive and carrier-mediated uptake by means of SMVT. The specific interactions between R.I.-K(biotin)-Tat9 and SMVT suggest that targeting approaches utilizing transporters such as SMVT may substantially improve the oral delivery of large peptides. 相似文献
In this study, we present a model for the gait of normal and Parkinson's disease (PD) persons. Gait is semi-periodic and has fractal properties. Sine circle map (SCM) relation has a sinusoidal term and can show chaotic behaviour. Therefore, we used SCM as a basis for our model structure. Moreover, some similarities exist between the parameters of this relation and basal ganglia (BG) structure. This relation can explain the complex behaviours and the complex structure of BG. The presented model can simulate the BG behaviour globally. A model parameter, Ω, has a key role in the model response. We showed that when Ω is between 0.6 and 0.8, the model simulates the behaviour of normal persons; the amounts greater or less than this range correspond to PD persons. Our statistical tests show that there is a significant difference between the Ω of normal and PD patients. We conclude that Ω can be introduced as a parameter to distinguish normal and PD persons. Additionally, our results showed that Spearman correlation between the Ω and the severity of PD is 0.586. This parameter may be a good index of PD severity. 相似文献
Stem cell transplantation is a promising new therapeutic option in different neurological diseases. However, it was not yet possible to translate its potential from animal models to clinical application. One of the main problems of applying stem cell transplantation in clinical medium is the difficulty of detection, localization, and examination of the stem cells in vivo at both cellular and molecular levels. State-of-the-art molecular imaging techniques provide new and better means for noninvasive, repeated, and quantitative tracking of stem cell implant or transplant. From initial deposition to the survival, migration, and differentiation of the transplant/implanted stem cells, current molecular imaging methods allow monitoring of the infused cells in the same live recipient over time. The present review briefly summarizes and compares these molecular imaging methods for cell labeling and imaging in animal models as well as in clinical application and sheds light on consecutive new therapeutic options if appropriate. 相似文献
Currently, the best treatment strategy for patients with a high‐normal blood pressure (prehypertension) is not known. The authors aimed to determine whether pharmacological reduction of systolic blood pressure (SBP) to a normal level (<120 mm Hg) would prevent cardiac morbidity and mortality in prehypertensive patients. In this secondary analysis, the authors obtained the data from SPRINT from the National Heart, Lung, and Blood Institute data repository center. Among 9361 patients enrolled in SPRINT, 289 high‐risk (ASCVD risk = 24.8% ± 13.0 [10‐65]) prehypertensive patients without previous cardiovascular disease and not receiving any antihypertensive medications were enrolled. One hundred and forty‐eight of them were assigned to standard treatment which consisted of clinical follow‐up till SBP goes above 140 mm Hg and then staring medications to keep SBP <140 mm Hg. One hundred and forty‐one were assigned to the intensive treatment receiving pharmacological SBP reduction to <120 mm Hg upon enrollment. The primary composite outcome was myocardial infarction, and other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. Throughout the 3.06 years of follow‐up, a primary outcome event was confirmed in three participants (0.74% per year) in the intensive‐treatment group and 8 (1.61% per year) in the standard‐treatment group (hazard ratio [HR], 0.19; P = .045). Rates of serious adverse events were not increased by intensive‐treatment (HR, 0.83; P = .506). Based on this secondary post hoc analysis, intensive SBP reduction may probably be beneficial for primary prevention of cardiovascular morbidity and mortality in high‐risk prehypertensive patients. This finding needs to be evaluated in a larger trial designed specifically to answer this question. 相似文献