Mutation-induced Blocker Permeability and Multiion Block of the CFTR Chloride Channel Pore

Chloride permeation through the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel is blocked by a broad range of anions that bind tightly within the pore. Here we show that the divalent anion Pt(NO2)42− acts as an impermeant voltage-dependent blocker of the CFTR pore when added to the intracellular face of excised membrane patches. Block was of modest affinity (apparent Kd 556 μM), kinetically fast, and weakened by extracellular Cl− ions. A mutation in the pore region that alters anion selectivity, F337A, but not another mutation at the same site that has no effect on selectivity (F337Y), had a complex effect on channel block by intracellular Pt(NO2)42− ions. Relative to wild-type, block of F337A-CFTR was weakened at depolarized voltages but strengthened at hyperpolarized voltages. Current in the presence of Pt(NO2)42− increased at very negative voltages in F337A but not wild-type or F337Y, apparently due to relief of block by permeation of Pt(NO2)42− ions to the extracellular solution. This “punchthrough” was prevented by extracellular Cl− ions, reminiscent of a “lock-in” effect. Relief of block in F337A by Pt(NO2)42− permeation was only observed for blocker concentrations above 300 μM; as a result, block at very negative voltages showed an anomalous concentration dependence, with an increase in blocker concentration causing a significant weakening of block and an increase in Cl− current. We interpret this effect as reflecting concentration-dependent permeability of Pt(NO2)42− in F337A, an apparent manifestation of an anomalous mole fraction effect. We suggest that the F337A mutation allows intracellular Pt(NO2)42− to enter deeply into the CFTR pore where it interacts with multiple binding sites, and that simultaneous binding of multiple Pt(NO2)42− ions within the pore promotes their permeation to the extracellular solution

Dependency Relationships-Enhanced Attentive Group Recommendation in HINs

Recommending suitable items to a group of users, commonly referred to as the group recommendation task, is becoming increasingly urgent with the development of group activities. The challenges within the group recommendation task involve aggregating the individual preferences of group members as the group's preferences and facing serious sparsity problems due to the lack of user/group-item interactions. To solve these problems, we propose a novel approach called Dependency Relationships-Enhanced Attentive Group Recommendation (DREAGR) for the recommendation task of occasional groups. Specifically, we introduce the dependency relationship between items as side information to enhance the user/group-item interaction and alleviate the interaction sparsity problem. Then, we propose a Path-Aware Attention Embedding (PAAE) method to model users' preferences on different types of paths. Next, we design a gated fusion mechanism to fuse users' preferences into their comprehensive preferences. Finally, we develop an attention aggregator that aggregates users' preferences as the group's preferences for the group recommendation task. We conducted experiments on two datasets to demonstrate the superiority of DREAGR by comparing it with state-of-the-art group recommender models. The experimental results show that DREAGR outperforms other models, especially HR@N and NDCG@N (N=5, 10), where DREAGR has improved in the range of 3.64% to 7.01% and 2.57% to 3.39% on both datasets, respectively.Comment: 14 pages, 9 figures, This paper has been submitted to IEEE Transactions on Knowledge and Data Engineerin

Antibody-Targeted Immunocarriers for Cancer Treatment

Nanocarrier’s engineering based on fine chemical design and novel structural tailoring can provide practical solution to solve the problems in traditional cancer immunotherapy. Nanoimmunotherapy is thus defined as the application and further development of novel nanocarriers for enhancing immunotherapy. It has become one of the most intriguing fields due to its unique power in treatment and even cure of cancer since reported in last year. Herein, this chapter illustrates the state-of-the-art development in antibody engineering and cancer immunotherapy and gives an explanation why functional nanocarries including micelles and liposomes can be efficient for nanoimmunotherapy. We further illustrate how to promote the nanoimmunotherapy by the chemical design and carrier’s engineering for the first time

Creating Visible-to-Near-Infrared Mechanoluminescence in Mixed-Anion Compounds SrZn 2 S 2 O and SrZnSO

Abstract(#br)Mechanoluminescence (ML) materials featuring light emission in response to mechanical stimulus have shown promising applications in damage diagnosis, dynamic force detection, and information storage. However, their applications are greatly limited by a very small number of available ML materials as well as unsatisfied ML spectra. In this paper, we developed novel ML materials with intense ML and super-broad visible-to-near-infrared (470-1600 nm) spectra by incorporating lanthanide ions or transition metals into mixed-anion compounds SrZn 2 S 2 O and SrZnSO. These mixed-anion compounds show a linear relationship between ML intensity and applied force, allowing them to be used in non-contact/multi-touch stress sensing. Moreover, the mixed-anion compounds exhibit multiband near-infrared ML enabling a significant bright-field stress sensing approach without the interference of ambient light. This work offers a unique insight for discovering new ML materials and enriching the ML spectral range, thereby promoting their potential applications in stress intelligent sensors, electronic skins, and human-machine interfaces

Dynamic Sealing Behavior of Sand Self-Juxtaposition Windows on a Trap-Bounding Fault in a Natural Gas Storage Site

AbstractAn understanding of across-fault seals is essential for planning an injection/production strategy for a fault-bounded gas storage site. In addition, it is more likely to permit lateral leakage for a fault with sand self-juxtaposition windows. This paper is aimed at identifying the dynamic sealing behaviors of a sand self-juxtaposition fault on the geological and gas injection timescales. Banzhongbei gas storage site, China, was taken as a target area, and fault seals and hydrocarbon distributions within the original reservoirs were studied. The results showed that across-fault pressure differences of 0.085~0.146 MPa (equivalent to 41.6~71.5 m oil-column and 27.0~46.4 m gas-column heights) were supported by sand self-juxtaposition windows on the B816 fault, and the resultant absolute permeability (5.97×10−2~5.69×10−1 mD) of the fault was nearly 3~4 orders of magnitude lower than the average absolute permeability of reservoirs (1.16×102 mD). Gas composition contrasts, between the original and injection gas coupled with dynamic pressure monitoring data, indicated that lateral leakage occurred across sand self-juxtaposition windows under the condition of high across-fault pressure difference. However, the low-permeability fault showed strong negative influence on the efficiency of fluid flow in the model calculations and prolongs the timescales of pressure-difference decayed as much as 5 orders of magnitude relative to those of nonfault model calculations. These modeled dynamic sealing behaviors of sand self-juxtaposition windows may lead to a better understanding of the relative retardation of across-fault gas flow by weak sealing faults on the gas injection/production timescale

Molecular mechanism of anion permeation through CFTR channel pore.

The proposed research in my lab has been focusing on the structure, function and molecular pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel; and the interaction of CFTR chloride channels with other ion channels, receptors in submucosal gland cells. Chronic lung infection and deterioration of lung function are the major causes of morbidity and death in cystic fibrosis (CF), the most common inherited lethal disease in Caucasians. Although the genetic defect in CF was discovered in 1989-mutations in the gene encoding the CFTR, the mechanism by which CFTR mutations cause lung disease remain uncertain. We arc very interested in studying a number of mechanisms proposed to link the CF genotype to clinical disease, particularly in defective airway submucosal gland secretion, loss of CFTR regulation of other transporting proteins such as other chloride channels, potassium channels, aquaporins in a serous epithelial cells. Determination of the mechanism linking genotype to disease is of crilical importance in developing therapies to treat CF

Optimisation and modelling of the growth and astaxanthin formation of haematococcus pluvialis

published_or_final_versionBotanyDoctoralDoctor of Philosoph

Multiple inhibitory effects of Au(CN)2− ions on cystic fibrosis transmembrane conductance regulator Cl− channel currents

Lyotropic pseudohalide anions are potentially useful as high affinity probes of Cl− channel pores. However, the interaction between these pseudohalides and the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel have not been described in detail. Here we show that Au(CN)2− ions applied to the intracellular face of membrane patches from stably transfected baby hamster kidney cells inhibit CFTR channel currents by at least two mechanisms, which can be distinguished at the single channel level or by inhibiting channel closure using 2 mm pyrophosphate. Low concentrations (< 10 μm) of Au(CN)2− significantly reduced CFTR channel open probability. This effect was apparently voltage insensitive, independent of extracellular Cl− concentration, and lost following exposure to pyrophosphate. Higher concentrations of intracellular Au(CN)2− caused an apparent reduction in unitary current amplitude, presumably due to a kinetically fast blocking reaction. This effect, isolated following exposure to pyrophosphate, was strongly voltage dependent (apparent Kd 61.6 μm at −100 mV and 913 μm at +60 mV). Both the affinity and voltage dependence of block were highly sensitive to extracellular Cl− concentration. We propose that Au(CN)2− has at least two inhibitory effects on CFTR currents: a high affinity effect on channel gating due to action on a cytoplasmically accessible aspect of the channel and a lower affinity block within the open channel pore. These results offer important caveats for the use of lyotropic pseudohalide anions such as Au(CN)2− as specific high affinity probes of Cl− channel pores

Submucosal gland ion channels and cystic fibrosis.

Cystic fibrosis (CF), the most common fatal genetic disease, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) [20, 22]. Since the CFTR gene was identified in 1989 [23], a lot of research effort has been focused on either replacing the defective gene or rescuing the function of mutant CFTR in CF patients [20, 22]. Overall, no currently approved treatment cures the disease [22]. Most of the morbidity and mortality of CF results from lung disease which involves devastating loss of transepithelial anion secretion [20, 28, 29]. In lung, CFTR is strongly expressed in submucosal glands, it has been suggested that these cells represent the primary site of cystic fibrosis pathology [1, 2]. Anion secretion in submucosal gland is mediated by CFTR cr channels at the apical membrane [4], however, other chloride channels may also involves and the net rate of secretion is determined by the activity of basolateral K+ channels.ARC 05/0