Segregated Nanocompartments Containing Therapeutic Enzymes and Imaging Compounds within DNA-Zipped Polymersome Clusters for Advanced Nanotheranostic Platform

Abstract Nanotheranostics is an emerging field that brings together nanoscale-engineered materials with biological systems providing a combination of therapeutic and diagnostic strategies. However, current theranostic nanoplatforms have serious limitations, mainly due to a mismatch between the physical properties of the selected nanomaterials and their functionalization ease, loading ability, or overall compatibility with bioactive molecules. Herein, a nanotheranostic system is proposed based on nanocompartment clusters composed of two different polymersomes linked together by DNA. Careful design and procedure optimization result in clusters segregating the therapeutic enzyme human Dopa decarboxylase (DDC) and fluorescent probes for the detection unit in distinct but colocalized nanocompartments. The diagnostic compartment provides a twofold function: trackability via dye loading as the imaging component and the ability to attach the cluster construct to the surface of cells. The therapeutic compartment, loaded with active DDC, triggers the cellular expression of a secreted reporter enzyme via production of dopamine and activation of dopaminergic receptors implicated in atherosclerosis. This two-compartment nanotheranostic platform is expected to provide the basis of a new treatment strategy for atherosclerosis, to expand versatility and diversify the types of utilizable active molecules, and thus by extension expand the breadth of attainable applications

Serum protein biomarkers for HCC risk prediction in HIV/HBV co-infected people: a clinical proteomic study using mass spectrometry

BackgroundHBV coinfection is frequent in people living with HIV (PLWH) and is the leading cause of hepatocellular carcinoma (HCC). While risk prediction methods for HCC in patients with HBV monoinfection have been proposed, suitable biomarkers for early diagnosis of HCC in PLWH remain uncommon.MethodsLiquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to examine serum protein alterations in HCC and non-HCC patients with HIV and HBV co-infection. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Disease Ontology (DO) enrichment analysis were performed on the differentially expressed proteins (DEPs). The risk prediction model was created using five-cross-validation and LASSO regression to filter core DEPs.ResultsA total of 124 DEPs were discovered, with 95 proteins up-regulated and 29 proteins down-regulated. Extracellular matrix organization and membrane component were the DEPs that were most abundant in the categories of biological processes (BP) and cellular components (CC). Proteoglycans in cancer were one of the top three DEPs primarily enriched in the KEGG pathway, and 60.0% of DEPs were linked to various neoplasms in terms of DO enrichment. Eleven proteins, including GAPR1, PLTP, CLASP2, IGHV1-69D, IGLV5-45, A2M, VNN1, KLK11, ANPEP, DPP4 and HYI, were chosen as the core DEPs, and a nomogram was created to predict HCC risk.ConclusionIn HIV/HBV patients with HCC, several differential proteins can be detected in plasma by mass spectrometry, which can be used as screening markers for early diagnosis and risk prediction of HCC. Monitoring protease expression differences can help in the diagnosis and prognosis of HCC

An Empirical Comparison of Information-Theoretic Criteria in Estimating the Number of Independent Components of fMRI Data

BACKGROUND: Independent Component Analysis (ICA) has been widely applied to the analysis of fMRI data. Accurate estimation of the number of independent components of fMRI data is critical to reduce over/under fitting. Although various methods based on Information Theoretic Criteria (ITC) have been used to estimate the intrinsic dimension of fMRI data, the relative performance of different ITC in the context of the ICA model hasn't been fully investigated, especially considering the properties of fMRI data. The present study explores and evaluates the performance of various ITC for the fMRI data with varied white noise levels, colored noise levels, temporal data sizes and spatial smoothness degrees. METHODOLOGY: Both simulated data and real fMRI data with varied Gaussian white noise levels, first-order auto-regressive (AR(1)) noise levels, temporal data sizes and spatial smoothness degrees were carried out to deeply explore and evaluate the performance of different traditional ITC. PRINCIPAL FINDINGS: Results indicate that the performance of ITCs depends on the noise level, temporal data size and spatial smoothness of fMRI data. 1) High white noise levels may lead to underestimation of all criteria and MDL/BIC has the severest underestimation at the higher Gaussian white noise level. 2) Colored noise may result in overestimation that can be intensified by the increase of AR(1) coefficient rather than the SD of AR(1) noise and MDL/BIC shows the least overestimation. 3) Larger temporal data size will be better for estimation for the model of white noise but tends to cause severer overestimation for the model of AR(1) noise. 4) Spatial smoothing will result in overestimation in both noise models. CONCLUSIONS: 1) None of ITC is perfect for all fMRI data due to its complicated noise structure. 2) If there is only white noise in data, AIC is preferred when the noise level is high and otherwise, Laplace approximation is a better choice. 3) When colored noise exists in data, MDL/BIC outperforms the other criteria

Parallel Alterations of Functional Connectivity during Execution and Imagination after Motor Imagery Learning

BACKGROUND: Neural substrates underlying motor learning have been widely investigated with neuroimaging technologies. Investigations have illustrated the critical regions of motor learning and further revealed parallel alterations of functional activation during imagination and execution after learning. However, little is known about the functional connectivity associated with motor learning, especially motor imagery learning, although benefits from functional connectivity analysis attract more attention to the related explorations. We explored whether motor imagery (MI) and motor execution (ME) shared parallel alterations of functional connectivity after MI learning. METHODOLOGY/PRINCIPAL FINDINGS: Graph theory analysis, which is widely used in functional connectivity exploration, was performed on the functional magnetic resonance imaging (fMRI) data of MI and ME tasks before and after 14 days of consecutive MI learning. The control group had no learning. Two measures, connectivity degree and interregional connectivity, were calculated and further assessed at a statistical level. Two interesting results were obtained: (1) The connectivity degree of the right posterior parietal lobe decreased in both MI and ME tasks after MI learning in the experimental group; (2) The parallel alterations of interregional connectivity related to the right posterior parietal lobe occurred in the supplementary motor area for both tasks. CONCLUSIONS/SIGNIFICANCE: These computational results may provide the following insights: (1) The establishment of motor schema through MI learning may induce the significant decrease of connectivity degree in the posterior parietal lobe; (2) The decreased interregional connectivity between the supplementary motor area and the right posterior parietal lobe in post-test implicates the dissociation between motor learning and task performing. These findings and explanations further revealed the neural substrates underpinning MI learning and supported that the potential value of MI learning in motor function rehabilitation and motor skill learning deserves more attention and further investigation

Identification of Sclareol As a Natural Neuroprotective Caᵥ1.3-Antagonist Using Synthetic Parkinson-Mimetic Gene Circuits and Computer-Aided Drug Discovery

Parkinson's disease (PD) results from selective loss of substantia nigra dopaminergic (SNc DA) neurons, and is primarily caused by excessive activity-related Ca2+ oscillations. Although L-type voltage-gated calcium channel blockers (CCBs) selectively inhibiting Ca(v)1.3 are considered promising candidates for PD treatment, drug discovery is hampered by the lack of high-throughput screening technologies permitting isoform-specific assessment of Cav-antagonistic activities. Here, a synthetic-biology-inspired drug-discovery platform enables identification of PD-relevant drug candidates. By deflecting Cav-dependent activation of nuclear factor of activated T-cells (NFAT)-signaling to repression of reporter gene translation, they engineered a cell-based assay where reporter gene expression is activated by putative CCBs. By using this platform in combination with in silico virtual screening and a trained deep-learning neural network, sclareol is identified from a essential oils library as a structurally distinctive compound that can be used for PD pharmacotherapy. In vitro studies, biochemical assays and whole-cell patch-clamp recordings confirmed that sclareol inhibits Ca(v)1.3 more strongly than Ca(v)1.2 and decreases firing responses of SNc DA neurons. In a mouse model of PD, sclareol treatment reduced DA neuronal loss and protected striatal network dynamics as well as motor performance. Thus, sclareol appears to be a promising drug candidate for neuroprotection in PD patients.ISSN:2198-384

Cosmetics-triggered percutaneous remote control of transgene expression in mice

Synthetic biology has significantly advanced the rational design of trigger-inducible gene switches that program cellular behavior in a reliable and predictable manner. Capitalizing on genetic componentry, including the repressor PmeR and its cognate operator OPmeR, that has evolved in Pseudomonas syringae pathovar tomato DC3000 to sense and resist plant-defence metabolites of the paraben class, we have designed a set of inducible and repressible mammalian transcription-control devices that could dose-dependently fine-tune transgene expression in mammalian cells and mice in response to paraben derivatives. With an over 60-years track record as licensed preservatives in the cosmetics industry, paraben derivatives have become a commonplace ingredient of most skin-care products including shower gels, cleansing toners and hand creams. As parabens can rapidly reach the bloodstream of mice following topical application, we used this feature to percutaneously program transgene expression of subcutaneous designer cell implants using off-the-shelf commercial paraben-containing skin-care cosmetics. The combination of non-invasive, transdermal and orthogonal trigger-inducible remote control of transgene expression may provide novel opportunities for dynamic interventions in future gene and cell-based therapies.ISSN:1362-4962ISSN:0301-561

Dynamic Changes in Anthocyanin Accumulation and Cellular Antioxidant Activities in Two Varieties of Grape Berries during Fruit Maturation under Different Climates

As popularly consumed fruit berries, grapes are widely planted and processed into products, such as raisins and wine. In order to identify the influences of different climatic conditions on grape coloring and quality formation, we selected two common varieties of grape berries, ‘Red Globe’ and ‘Xin Yu’, for investigation. Grapes were separately grown in different climates, such as a temperate continental arid climate and a temperate continental desert climate, in Urumqi and Turpan, China, for five developmental stages. As measured, the average daily temperature and light intensity were lower in Urumqi. Urumqi grape berries had a lower brightness value (L*) and a higher red-green value (a*) when compared to Turpan’s. A RT-qPCR analysis revealed higher transcriptions of key genes related to anthocyanin biosynthesis in Urumqi grape berries, which was consistent with the more abundant phenolic substances, especially anthocyanins. The maximum antioxidant activity in vitro and cellular antioxidant activity of grape berries were also observed in Urumqi grape berries. These findings enclosed the influence of climate on anthocyanin accumulation and the antioxidant capacity of grapes, which might enlarge our knowledge on the quality formation of grape berries and might also be helpful for cultivating grapes with higher nutritional value