Study of brain network alternations in non-lesional epilepsy patients by BOLD-fMRI

ObjectiveTo investigate the changes of brain network in epilepsy patients without intracranial lesions under resting conditions.MethodsTwenty-six non-lesional epileptic patients and 42 normal controls were enrolled for BOLD-fMRI examination. The differences in brain network topological characteristics and functional network connectivity between the epilepsy group and the healthy controls were compared using graph theory analysis and independent component analysis.ResultsThe area under the curve for local efficiency was significantly lower in the epilepsy patients compared with healthy controls, while there were no differences in global indicators. Patients with epilepsy had higher functional connectivity in 4 connected components than healthy controls (orbital superior frontal gyrus and medial superior frontal gyrus, medial superior frontal gyrus and angular gyrus, superior parietal gyrus and paracentral lobule, lingual gyrus, and thalamus). In addition, functional connectivity was enhanced in the default mode network, frontoparietal network, dorsal attention network, sensorimotor network, and auditory network in the epilepsy group.ConclusionThe topological characteristics and functional connectivity of brain networks are changed in in non-lesional epilepsy patients. Abnormal functional connectivity may suggest reduced brain efficiency in epilepsy patients and also may be a compensatory response to brain function early at earlier stages of the disease

Engineering grain boundaries at the 2D limit for the hydrogen evolution reaction

Atom-thin transition metal dichalcogenides (TMDs) have emerged as fascinating materials and key structures for electrocatalysis. So far, their edges, dopant heteroatoms and defects have been intensively explored as active sites for the hydrogen evolution reaction (HER) to split water. However, grain boundaries (GBs), a key type of defects in TMDs, have been overlooked due to their low density and large structural variations. Here, we demonstrate the synthesis of wafer-size atom-thin TMD films with an ultra-high-density of GBs, up to ~1012 cm−2. We propose a climb and drive 0D/2D interaction to explain the underlying growth mechanism. The electrocatalytic activity of the nanograin film is comprehensively examined by micro-electrochemical measurements, showing an excellent hydrogen-evolution performance (onset potential: −25 mV and Tafel slope: 54 mV dec−1), thus indicating an intrinsically high activation of the TMD GBs

Protein and Ligand Interactions of MYC Promoter Gquadruplex

G-quadruplexes (G4s) are non-canonical secondary structures formed in single-stranded guanine-rich nucleic acid sequences, such as those found in oncogene promoters and telomeres. MYC, one of the most critical oncogenes, has a DNA G4 (MYCG4) in its proximal promoter region that functions as a transcriptional silencer. MYCG4 is very stable and the pathological activation of MYC requires its active unfolding. However, it remains unclear what drives MYCG4 unfolding in cancer cells. We have studied the interactions of DDX5 with the MYCG4 at both molecular and cellular levels and discovered that DDX5 actively unfolds the MYCG4 and is involved in the MYC gene transcriptional regulation, which is described in the first part of this dissertation. DDX5 is extremely proficient at unfolding the MYCG4 and ATP hydrolysis is not directly coupled to the G4-unfolding of DDX5. In cancer cells, DDX5 is enriched at the MYC promoter and activates MYC transcription. G4-interactive small molecules inhibit the DDX5 interaction with the MYC promoter and DDX5-mediated MYC activation. The second part of this dissertation describes the study of interactions of indenoisoquinoline anticancer drugs with MYCG4. The MYCG4 transcriptional silencer is a very attractive therapeutic target. Compounds that bind and stabilize the MYCG4 have been shown to repress MYC gene transcription and are antitumorigenic. Indenoisoquinolines are human topoisomerase I inhibitors in clinical testing. However, some indenoisoquinolines with potent anticancer activity do not exhibit strong topoisomerase I inhibition, suggesting a separate mechanism of action. Our studies show that indenoisoquinolines strongly bind and stabilize MYCG4 and lower MYC levels in cancer cells. Moreover, the analysis of indenoisoquinoline analogues for their MYC inhibitory activity, topoisomerase I inhibitory activity, and anticancer activity reveals a synergistic effect of MYC inhibition and topoisomerase I inhibition on anticancer activity. Besides the MYCG4, human telomeric G4s are also attractive targets for anticancer drugs due to their ability to inhibit telomere extension in cancer cells. The last part of this dissertation reviews two recent solution structural studies on small molecule complexes with the hybrid-2 telomeric G4 and the hybrid-1 telomeric G4. Structural information of those complexes can advance the design of telomeric G4-interactive small molecules in the cancer therapeutic areas

Molecular Recognition of the Hybrid-Type G-Quadruplexes in Human Telomeres

G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form two hybrid-type G-quadruplexes, namely hybrid-1 and hybrid-2, under physiologically relevant solution conditions. To date, only a handful solution structures are available for drug complexes of human telomeric G-quadruplexes. In this review, we will describe two recent solution structural studies from our labs. We use NMR spectroscopy to elucidate the solution structure of a 1:1 complex between a small molecule epiberberine and the hybrid-2 telomeric G-quadruplex, and the structures of 1:1 and 4:2 complexes between a small molecule Pt-tripod and the hybrid-1 telomeric G-quadruplex. Structural information of small molecule complexes can provide important information for understanding small molecule recognition of human telomeric G-quadruplexes and for structure-based rational drug design targeting human telomeric G-quadruplexes

Dynamic control simulation of steam test system boundary based on GSE platform

[Objectives] The bench test is an important means for the design and verification of steam systems,and the accuracy of the boundary condition is a critical factor for studying the characteristics of the bench test.[Methods] In order to propose a feasible dynamic flow boundary control method,based on the change requirements of steam inlet flow in the bench test of a steam system,the two schemes of PID closed-loop control and open-loop control are proposed,and simulation comparison and analysis are carried out. In the GSE simulation system,JTopmeret modules are employed to establish the whole steam test system,the optimization of the modules and correction of parameters are processed on the basis of the data detected in the steam test,and the simulation data is compared with the experimental data to verify the accuracy and validity of the simulation model.[Results] For the control requirements of reducing steam flow linearly by 20 t/h within 10 s,the simulation results show that the open-loop control scheme allows the control of boundary conditions to be achieved after several iterations,while using the traditional PID closed-loop control scheme makes it difficult to control the boundary as required. The test results show that the flow change at the steam inlet meets the test requirements of the bench test,and is consistent with the simulation results.[Conclusions] The results of this research can provide references for the boundary control of steam system bench tests

Structures of 1:1 and 2:1 complexes of BMVC and MYC promoter G-quadruplex reveal a mechanism of ligand conformation adjustment for G4-recognition

BMVC is the first fluorescent probe designed to detect G-quadruplexes (G4s) in vivo. The MYC oncogene promoter forms a G4 (MycG4) which acts as a transcription silencer. Here, we report the high-affinity and specific binding of BMVC to MycG4 with unusual slow-exchange rates on the NMR timescale. We also show that BMVC represses MYC in cancer cells. We determined the solution structures of the 1:1 and 2:1 BMVC-MycG4 complexes. BMVC first binds the 5'-end of MycG4 to form a 1:1 complex with a well-defined structure. At higher ratio, BMVC also binds the 3'-end to form a second complex. In both complexes, the crescent-shaped BMVC recruits a flanking DNA residue to form a BMVC-base plane stacking over the external G-tetrad. Remarkably, BMVC adjusts its conformation to a contracted form to match the G-tetrad for an optimal stacking interaction. This is the first structural example showing the importance of ligand conformational adjustment in G4 recognition. BMVC binds the more accessible 5'-end with higher affinity, whereas sequence specificity is present at the weaker-binding 3'-site. Our structures provide insights into specific recognition of MycG4 by BMVC and useful information for design of G4-targeted anticancer drugs and fluorescent probes.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity

G-quadruplexes (G4) are considered new drug targets for human diseases such as cancer. More than 10,000 G4s have been discovered in human chromatin, posing challenges for assessing the selectivity of a G4-interactive ligand. 3,6-bis(1-Methyl-4-vinylpyridinium) carbazole diiodide (BMVC) is the first fluorescent small molecule for G4 detection in vivo. Our previous structural study shows that BMVC binds to the MYC promoter G4 (MycG4) with high specificity. Here, we utilize high-throughput, large-scale custom DNA G4 microarrays to analyze the G4-binding selectivity of BMVC. BMVC preferentially binds to the parallel MycG4 and selectively recognizes flanking sequences of parallel G4s, especially the 3′-flanking thymine. Importantly, the microarray results are confirmed by orthogonal NMR and fluorescence binding analyses. Our study demonstrates the potential of custom G4 microarrays as a platform to broadly and unbiasedly assess the binding selectivity of G4-interactive ligands, and to help understand the properties that govern molecular recognition

Stratigraphic lithology identification based on no-dig Logging While Drilling system and random forest

Through the self-developed and designed no-dig Logging While Drilling(LWD) system, it can collect the parameters of no-dig drilling, identify the real-time formation lithology of no-dig drilling, and provide safety information guarantee for no-dig construction.In view of the lack of prospecting data in no-dig engineering, it is difficult to determine the lithology of the excavation stratum.A real-time data acquisition system based on the no-dig LWD system is proposed.The random forest algorithm is used to establish the stratum identification model, and identify the unknown strata.The identification results are displayed visually.Through the practical application of the detection while drilling system in the engineering field, the drilling sensitive parameters including Rate of Penetration(ROP), torque, rotation speed, pulling force, pump pressure and pump volume are obtained as training samples.The random forest algorithm is used to train the collected drilling parameters, and the decision tree and random forest are constructed to classify the drilling parameters.A classification model aiming at the classification of typical no-dig strata is established, and the classification labels of miscellaneous fill, clay, silty fine sand, gravel and silt are determined respectively.Furthermore, based on the classification results of machine learning, PCA principal component analysis is used to reduce the dimension of strata recognition features to three-dimensional, and realize the three-dimensional display of formation lithology identification results.The prediction model is applied to practical engineering to verify its effectiveness.The results show that the method can quickly identify the drilling formation under the condition of no-dig real-time drilling, and the recognition accuracy is as high as 92%.The research results provide important information for the selection of no-dig mud and no-dig reaming stage

Combination of Multifocal Electroretinogram and Spectral-Domain OCT Can Increase Diagnostic Efficacy of Parkinson’s Disease

Background. The retinal changes have been identified in morphology and function in Parkinson’s disease (PD). However, the controversial results suggest that it is incredible that only using a single method for testing retinal change to evaluate Parkinson’s disease. The aim of this study was to assess retinal changes and increase the diagnostic efficacy of Parkinson’s disease with a combination of multifocal electroretinogram (mf-ERG) and spectral domain optical coherence tomography (SD-OCT) examinations. Method. Fifty-three PD patients and forty-one healthy controls were enrolled. Subjects were assessed for retinal function using mf-ERG and retinal structure using SD-OCT. Results. The PD patients had a significantly decreased amplitude density of P1 and a delayed implicit time of P1 in some regions. The macular retinal thickness, macular volume, and average RNFL thickness were decreased in PD. The AUC of a single parameter of either retinal function or structure was low. Both of them were higher in diagnostic value to discriminate PD patients. Conclusion. The amplitude density of P1 combined with macular volume can get a high diagnostic efficacy to discriminate between participants with or without PD. It indicates that a combination of mf-ERG and SD-OCT provides a good clinical biomarker for diagnosis of PD