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1.
The anoctamin (TMEM16) family of transmembrane protein consists of ten members in vertebrates, which act as Ca2+-dependent ion channels and/or Ca2+-dependent scramblases. ANO4 which is primarily expressed in the CNS and certain endocrine glands, has been associated with various neuronal disorders. Therefore, we focused our study on prioritizing missense mutations that are assumed to alter the structure and stability of ANO4 protein. We employed a wide array of evolution and structure based in silico prediction methods to identify potentially deleterious missense mutations in the ANO4 gene. Identified pathogenic mutations were then mapped to the modeled human ANO4 structure and the effects of missense mutations were studied on the atomic level using molecular dynamics simulations. Our data show that the G80A and A500T mutations significantly alter the stability of the mutant proteins, thus providing new perspective on the role of missense mutations in ANO4 gene. Results obtained in this study may help to identify disease associated mutations which affect ANO4 protein structure and function and might facilitate future functional characterization of ANO4.  相似文献   
2.
Microtomography (μCT) and nuclear magnetic resonance (NMR) have been used to characterize porous media for decades. Magnetic resonance imaging (MRI) enables direct visualization of pore architecture and many pulse sequences exist. In this work, we tested the MRI pulse sequence Zero Echo Time (ZTE) to study sandstone and carbonate for its ability to address short relaxation times. We aimed at resolving two fluid conduit scales, that is, pores and fractures. In this research, we study tighter porous systems than those previously reported using ZTE. Additionally, pore cluster analysis (PCA), combined with ZTE, can be used to analyze pore-fracture connectivity of relatively large core plugs. We show that ZTE can resolve two-scale pore systems simultaneously, that is, fractures and pores. By combining time-domain NMR pore-size analysis and PCA, we show that careful selection of resolution is necessary to understand transport in porous media.  相似文献   
3.
Ceria-based solid solutions are important materials for high- and medium-temperature electrochemical applications. However, the stabilities of both binary and ternary ceria-based solid solutions are insufficient at elevated temperatures, which limits their application as solid electrolytes or SOFC cathodes. Data on the high-temperature stability of ceria-based ceramics are unavailable in the literature. In the present study, we report a thermodynamic stability investigation of Y2O3-CeO2 and Y2O3-ZrO2-CeO2 solid solutions. The thermal prehistories of binary and ternary systems were investigated using STA, XRD, and ESCA techniques. The vaporization processes were investigated in the temperature range of 1577–2227°С via the Knudsen effusion mass spectrometry technique. Using data on the component activity in solid-phase thermodynamic properties of Y2O3-CeO2 solid solutions, which is represented as the Gibbs energy, the excess Gibbs energy was calculated as a function of the ceria mol. %. It was shown that the reduction of Ce4+ to Ce3+ in Y2O3-CeO2 and Y2O3-ZrO2-CeO2 solid solutions corresponds to less-negative Gibbs energy compared to ZrO2-CeO2 solid solutions.  相似文献   
4.
The observation of the immunomodulatory effects of opioid drugs opened the discussion about possible mechanisms of action and led researchers to consider the presence of opioid receptors (OR) in cells of the immune system. To date, numerous studies analyzing the expression of OR subtypes in animal and human immune cells have been performed. Some of them confirmed the expression of OR at both the mRNA and protein level, while others did not detect the receptor mRNA either. Although this topic remains controversial, further studies are constantly being published. The most recent articles suggested that the expression level of OR in human peripheral blood lymphocytes could help to evaluate the success of methadone maintenance therapy in former opioid addicts, or could serve as a biomarker for chronic pain diagnosis. However, the applicability of these findings to clinical practice needs to be verified by further investigations.  相似文献   
5.
Recent evidence suggests that fibrotic liver injury in patients with chronic hepatitis C correlates with cellular senescence in damaged liver tissue. However, it is still unclear how senescence can affect replication of the hepatitis C virus (HCV). In this work, we report that an inhibitor of cyclin-dependent kinases 4/6, palbociclib, not only induced in hepatoma cells a pre-senescent cellular phenotype, including G1 arrest in the cell cycle, but also accelerated viral replicon multiplication. Importantly, suppression of HCV replication by direct acting antivirals (DAAs) was barely affected by pre-senescence induction, and vice versa, the antiviral activities of host-targeting agents (HTAs), such as inhibitors of human histone deacetylases (HDACi), produced a wide range of reactions—from a dramatic reduction to a noticeable increase. It is very likely that under conditions of the G1 arrest in the cell cycle, HDACi exhibit their actual antiviral potency, since their inherent anticancer activity that complicates the interpretation of test results is minimized.  相似文献   
6.
Radionuclide imaging of HER2 expression in tumours may enable stratification of patients with breast, ovarian, and gastroesophageal cancers for HER2-targeting therapies. A first-generation HER2-binding affibody molecule [99mTc]Tc-ZHER2:V2 demonstrated favorable imaging properties in preclinical studies. Thereafter, the affibody scaffold has been extensively modified, which increased its melting point, improved storage stability, and increased hydrophilicity of the surface. In this study, a second-generation affibody molecule (designated ZHER2:41071) with a new improved scaffold has been prepared and characterized. HER2-binding, biodistribution, and tumour-targeting properties of [99mTc]Tc-labelled ZHER2:41071 were investigated. These properties were compared with properties of the first-generation affibody molecules, [99mTc]Tc-ZHER2:V2 and [99mTc]Tc-ZHER2:2395. [99mTc]Tc-ZHER2:41071 bound specifically to HER2 expressing cells with an affinity of 58 ± 2 pM. The renal uptake for [99mTc]Tc-ZHER2:41071 and [99mTc]Tc-ZHER2:V2 was 25–30 fold lower when compared with [99mTc]Tc-ZHER2:2395. The uptake in tumour and kidney for [99mTc]Tc-ZHER2:41071 and [99mTc]Tc-ZHER2:V2 in SKOV-3 xenografts was similar. In conclusion, an extensive re-engineering of the scaffold did not compromise imaging properties of the affibody molecule labelled with 99mTc using a GGGC chelator. The new probe, [99mTc]Tc-ZHER2:41071 provided the best tumour-to-blood ratio compared to HER2-imaging probes for single photon emission computed tomography (SPECT) described in the literature so far. [99mTc]Tc-ZHER2:41071 is a promising candidate for further clinical translation studies.  相似文献   
7.
8.
This work presents a detailed study on the effect of various functional groups both at the ortho position of the aromatic ring and in the amino group of PANI on the antibacterial properties of polymers against gram-positive (Bacillus subtilis) and gram-negative (Pseudomonas aureofaciens) microorganisms. It was found that incorporation of methyl, methoxy, or pentyl groups into the ortho-position of PANI did not increase the antibacterial activity but in most cases causes a significant decrease in the antibacterial properties of functionally substituted polyanilines. At the same time, PANI derivatives modified by incorporation of pentyl groups into the amino group were found to be more efficient antibacterial compounds against both gram-positive and gram-negative microorganisms than the original polymer. It was also found that N-substituted PANI derivatives manifest not only bactericidal but also bacteriostatic properties toward the test microorganisms. Varying the nature and position of the substituent allowed us to conclude that the synthesis of various N-substituted PANI derivatives with a high degree of doping is the most promising approach to PANI modification for application in bacterial growth inhibition.  相似文献   
9.
The base and nucleotide excision repair pathways (BER and NER, respectively) are two major mechanisms that remove DNA lesions formed by the reactions of genotoxic intermediates with cellular DNA. It is generally believed that small non-bulky oxidatively generated DNA base modifications are removed by BER pathways, whereas DNA helix-distorting bulky lesions derived from the attack of chemical carcinogens or UV irradiation are repaired by the NER machinery. However, existing and growing experimental evidence indicates that oxidatively generated DNA lesions can be repaired by competitive BER and NER pathways in human cell extracts and intact human cells. Here, we focus on the interplay and competition of BER and NER pathways in excising oxidatively generated guanine lesions site-specifically positioned in plasmid DNA templates constructed by a gapped-vector technology. These experiments demonstrate a significant enhancement of the NER yields in covalently closed circular DNA plasmids (relative to the same, but linearized form of the same plasmid) harboring certain oxidatively generated guanine lesions. The interplay between the BER and NER pathways that remove oxidatively generated guanine lesions are reviewed and discussed in terms of competitive binding of the BER proteins and the DNA damage-sensing NER factor XPC-RAD23B to these lesions.  相似文献   
10.
Lithium (Li) metal anodes promise an ultrahigh theoretical energy density and low redox potential,thus being the critical energy material for next-generation batteries.Unfortunately,the formation of Li den-drites in Li metal anodes remarkably hinders the practical applications of Li metal anodes.Herein,the dynamic evolution of discrete Li dendrites and aggregated Li dendrites with increasing current densities is visualized by in-situ optical microscopy in conjunction with ex-situ scanning electron microscopy.As revealed by the phase field simulations,the formation of aggregated Li dendrites under high current den-sity is attributed to the locally concentrated electric field rather than the depletion of Li ions.More specif-ically,the locally concentrated electric field stems from the spatial inhomogeneity on the Li metal surface and will be further enhanced with increasing current densities.Adjusting the above two factors with the help of the constructed phase field model is able to regulate the electrodeposited morphology from aggregated Li dendrites to discrete Li dendrites,and ultimately columnar Li morphology.The methodol-ogy and mechanistic understanding established herein give a significant step toward the practical appli-cations of Li metal anodes.  相似文献   
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