scholarly journals Structure and lipid-mediated remodelling mechanism of the Na+/H+ exchanger NHA2

2021 ◽  
Author(s):  
Rei Matsuoka ◽  
Roman Fudim ◽  
Sukkyeong Jung ◽  
Chenou Zhang ◽  
Andre Bazzone ◽  
...  
Keyword(s):  
Ion Exchange ◽  
Structural Information ◽  
Salt Bridge ◽  
Structural Similarity ◽  
Ion Binding ◽  
Transport Activity ◽  
Regulation Of Transport ◽  
Fine Tune ◽  
Exchange Activity

Na+/H+ exchangers catalyse an ion-exchange activity that is carried out in most, if not all cells. SLC9B2, also known as NHA2, correlates with the long-sought after sodium/lithium (Na+/Li+) exchanger linked to the pathogenesis of diabetes mellitus and essential hypertension in humans. Despite its functional importance, structural information and the molecular basis of its ion-exchange mechanism have been lacking. Here, we report the cryo EM structures of bison NHA2 in detergent and in nanodiscs at 3.0 and 3.5 Å resolution, respectively. NHA2 shares closest structural similarity to the bacterial electrogenic Na+/H+ antiporter NapA, rather than other mammalian SLC9A members. Nevertheless, SSM-based electrophysiology results with NHA2 show the catalysis of electroneutral rather than electrogenic ion exchange, and the ion binding site is quite distinctive, with a tryptophan arginine-glutamate triad separated from the well established ion-binding aspartates. These triad residues fine-tune ion binding specificity, as demonstrated by a salt-bridge swap mutant that converts NHA2 into a Li+ specific transporter. Strikingly, an additional N terminal helix in NHA2 establishes a unique homodimer with a large ~ 25 Å intracellular gap between protomers. In the presence of phosphatidylinositol lipids, the N-terminal helix rearranges and closes this gap. We confirm that dimerization of NHA2 is required for activity in vivo, and propose that the N- terminal helix has evolved as a lipid-mediated remodelling switch for regulation of transport activity.

scholarly journals Allosteric Regulation of Transport Activity by Heterotrimerization of Arabidopsis Ammonium Transporter Complexes in Vivo

2013 ◽  
Vol 25 (3) ◽  
pp. 974-984 ◽  
Author(s):  
Lixing Yuan ◽  
Riliang Gu ◽  
Yuanhu Xuan ◽  
Erika Smith-Valle ◽  
Dominique Loqué ◽  
...  
Keyword(s):  
Allosteric Regulation ◽  
Ammonium Transporter ◽  
Transport Activity ◽  
Regulation Of Transport

scholarly journals A Novel Method to Predict Drug-Target Interactions Based on Large-Scale Graph Representation Learning

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2111
Author(s):  
Bo-Wei Zhao ◽  
Zhu-Hong You ◽  
Lun Hu ◽  
Zhen-Hao Guo ◽  
Lei Wang ◽  
...  
Keyword(s):  
Drug Target ◽  
Large Scale ◽  
Computational Models ◽  
Structural Information ◽  
Characteristic Curve ◽  
Representation Learning ◽  
Graph Representation ◽  
Convolutional Network ◽  
Novel Method

Identification of drug-target interactions (DTIs) is a significant step in the drug discovery or repositioning process. Compared with the time-consuming and labor-intensive in vivo experimental methods, the computational models can provide high-quality DTI candidates in an instant. In this study, we propose a novel method called LGDTI to predict DTIs based on large-scale graph representation learning. LGDTI can capture the local and global structural information of the graph. Specifically, the first-order neighbor information of nodes can be aggregated by the graph convolutional network (GCN); on the other hand, the high-order neighbor information of nodes can be learned by the graph embedding method called DeepWalk. Finally, the two kinds of feature are fed into the random forest classifier to train and predict potential DTIs. The results show that our method obtained area under the receiver operating characteristic curve (AUROC) of 0.9455 and area under the precision-recall curve (AUPR) of 0.9491 under 5-fold cross-validation. Moreover, we compare the presented method with some existing state-of-the-art methods. These results imply that LGDTI can efficiently and robustly capture undiscovered DTIs. Moreover, the proposed model is expected to bring new inspiration and provide novel perspectives to relevant researchers.

scholarly journals Actin and Microtubules Differently Contribute to Vacuolar Targeting Specificity during the Export from the ER

Membranes ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 299
Author(s):  
Monica De Caroli ◽  
Fabrizio Barozzi ◽  
Luciana Renna ◽  
Gabriella Piro ◽  
Gian-Pietro Di Sansebastiano
Keyword(s):  
Spatial Targeting ◽  
Traffic Regulation ◽  
Emergent Features ◽  
Vacuolar Sorting ◽  
Er Export ◽  
Golgi Network ◽  
Relationship Of ◽  
The Relationship ◽  
Fine Tune

Plants rely on both actin and microtubule cytoskeletons to fine-tune sorting and spatial targeting of membranes during cell growth and stress adaptation. Considerable advances have been made in recent years in the comprehension of the relationship between the trans-Golgi network/early endosome (TGN/EE) and cytoskeletons, but studies have mainly focused on the transport to and from the plasma membrane. We address here the relationship of the cytoskeleton with different endoplasmic reticulum (ER) export mechanisms toward vacuoles. These emergent features of the plant endomembrane traffic are explored with an in vivo approach, providing clues on the traffic regulation at different levels beyond known proteins’ functions and interactions. We show how traffic of vacuolar markers, characterized by different vacuolar sorting determinants, diverges at the export from the ER, clearly involving different components of the cytoskeleton.

scholarly journals N-palmitoyl-D-glucosamine, A Natural Monosaccharide-Based Glycolipid, Inhibits TLR4 and Prevents LPS-Induced Inflammation and Neuropathic Pain in Mice

2021 ◽  
Vol 22 (3) ◽  
pp. 1491 ◽  
Author(s):  
Monica Iannotta ◽  
Carmela Belardo ◽  
Maria Consiglia Trotta ◽  
Fabio Arturo Iannotti ◽  
Rosa Maria Vitale ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Inflammatory Cytokines ◽  
Lipid A ◽  
Saturated Fatty Acids ◽  
Structural Similarity ◽  
Antagonistic Activity ◽  
Critical Function ◽  
Anti Inflammatory

Toll-like receptors (TLRs) are key receptors through which infectious and non-infectious challenges act with consequent activation of the inflammatory cascade that plays a critical function in various acute and chronic diseases, behaving as amplification and chronicization factors of the inflammatory response. Previous studies have shown that synthetic analogues of lipid A based on glucosamine with few chains of unsaturated and saturated fatty acids, bind MD-2 and inhibit TLR4 receptors. These synthetic compounds showed antagonistic activity against TLR4 activation in vitro by LPS, but little or no activity in vivo. This study aimed to show the potential use of N-palmitoyl-D-glucosamine (PGA), a bacterial molecule with structural similarity to the lipid A component of LPS, which could be useful for preventing LPS-induced tissue damage or even peripheral neuropathies. Molecular docking and molecular dynamics simulations showed that PGA stably binds MD-2 with a MD-2/(PGA)3 stoichiometry. Treatment with PGA resulted in the following effects: (i) it prevented the NF-kB activation in LPS stimulated RAW264.7 cells; (ii) it decreased LPS-induced keratitis and corneal pro-inflammatory cytokines, whilst increasing anti-inflammatory cytokines; (iii) it normalized LPS-induced miR-20a-5p and miR-106a-5p upregulation and increased miR-27a-3p levels in the inflamed corneas; (iv) it decreased allodynia in peripheral neuropathy induced by oxaliplatin or formalin, but not following spared nerve injury of the sciatic nerve (SNI); (v) it prevented the formalin- or oxaliplatin-induced myelino-axonal degeneration of sciatic nerve. SIGNIFICANCE STATEMENT We report that PGA acts as a TLR4 antagonist and this may be the basis of its potent anti-inflammatory activity. Being unique because of its potency and stability, as compared to other similar congeners, PGA can represent a tool for the optimization of new TLR4 modulating drugs directed against the cytokine storm and the chronization of inflammation.

Fused Image Quality Measure Based on Structural Similarity

2011 ◽  
Vol 255-260 ◽  
pp. 2072-2076
Author(s):  
Yi Yong Han ◽  
Jun Ju Zhang ◽  
Ben Kang Chang ◽  
Yi Hui Yuan ◽  
Hui Xu
Keyword(s):  
Image Fusion ◽  
Structural Information ◽  
Similarity Index ◽  
Structural Similarity ◽  
Reference Image ◽  
Human Visual Perception ◽  
Subjective Evaluations ◽  
Fused Image ◽  
Fusion Methods ◽  
Image Quality Measure

Under the assumption that human visual perception is highly adapted for extracting structural information from a scene, we present a new approach using structural similarity index for assessing quality in image fusion. The advantages of our measures are that they do not require a reference image and can be easily computed. Numerous simulations demonstrate that our measures are conform to subjective evaluations and can be able to assess different image fusion methods.

scholarly journals Impact of Ceftiofur Administration in Steers on the Prevalence and Antimicrobial Resistance of Campylobacter spp.

2021 ◽  
Vol 9 (2) ◽  
pp. 318
Author(s):  
Sicun Fan ◽  
Derek Foster ◽  
William G. Miller ◽  
Jason Osborne ◽  
Sophia Kathariou
Keyword(s):  
Antimicrobial Resistance ◽  
Bacterial Resistance ◽  
Active Drug ◽  
Free Acid ◽  
Structural Similarity ◽  
Drug Concentrations ◽  
Pre Treatment ◽  
Ceftiofur Hydrochloride ◽  
Campylobacter Spp

Bacterial resistance to ceftiofur raises health concerns due to ceftiofur’s extensive veterinary usage and structural similarity with the human antibiotic ceftriaxone. Ceftiofur crystalline-free acid (CCFA) and ceftiofur hydrochloride (CHCL) are ceftiofur types used therapeutically in cattle, but their potential impacts on Campylobacter prevalence and antimicrobial resistance remain unclear. In this study two groups of steers were each treated with CCFA or CHCL. In vivo active drug concentrations were measured and fecal samples were analyzed for Campylobacter for up to 42 days post-treatment. Following administration, the colonic concentration of ceftiofur initially increased then dropped to pre-treatment levels by day 8. The estimated prevalence of Campylobacter spp. was significantly (p = 0.0009) higher during the first week after CCFA treatment than after CHCL treatment (81.3% vs. 45.2%). Campylobacter jejuni predominated overall, with other Campylobacter spp. mainly identified in the first week after CCFA treatment. No treatment impacts were noted on ceftiofur minimum inhibitory concentration (MIC) for C. jejuni (10–20 μg/mL). More C. jejuni genotypes were detected in CCFA-treated than CHCL-treated steers. These findings suggest that ceftiofur did not significantly impact Campylobacter prevalence or ceftiofur MIC. However, CHCL may be preferable due to the lower likelihood of temporary increases in Campylobacter prevalence.

scholarly journals Effects of Ubiquinol-10 on MicroRNA-146a Expression In Vitro and In Vivo

2009 ◽  
Vol 2009 ◽  
pp. 1-7 ◽  
Author(s):  
Constance Schmelzer ◽  
Mitsuaki Kitano ◽  
Gerald Rimbach ◽  
Petra Niklowitz ◽  
Thomas Menke ◽  
...  
Keyword(s):  
Gene Expression ◽  
Reactive Oxygen Species ◽  
Biological Processes ◽  
Oxygen Species ◽  
Moderate Reduction ◽  
Suppression Of Gene Expression ◽  
Fine Tune ◽  
Dependent Pathway

MicroRNAs (miRs) are involved in key biological processes via suppression of gene expression at posttranscriptional levels. According to their superior functions, subtle modulation of miR expression by certain compounds or nutrients is desirable under particular conditions. Bacterial lipopolysaccharide (LPS) induces a reactive oxygen species-/NF-κB-dependent pathway which increases the expression of the anti-inflammatory miR-146a. We hypothesized that this induction could be modulated by the antioxidant ubiquinol-10. Preincubation of human monocytic THP-1 cells with ubiquinol-10 reduced the LPS-induced expression level of miR-146a to 78.9±13.22%. In liver samples of mice injected with LPS, supplementation with ubiquinol-10 leads to a reduction of LPS-induced miR-146a expression to 78.12±21.25%. From these consistent in vitro and in vivo data, we conclude that ubiquinol-10 may fine-tune the inflammatory response via moderate reduction of miR-146a expression.

scholarly journals Screening marine algae metabolites as high-affinity inhibitors of SARS-CoV-2 main protease (3CLpro): an in silico analysis to identify novel drug candidates to combat COVID-19 pandemic

2020 ◽  
Vol 63 (1) ◽  
Author(s):  
Ghazala Muteeb ◽  
Adil Alshoaibi ◽  
Mohammad Aatif ◽  
Md. Tabish Rehman ◽  
M. Zuhaib Qayyum
Keyword(s):  
Hydrophobic Interactions ◽  
In Silico Analysis ◽  
Salt Bridge ◽  
Competitive Inhibitor ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
In Vivo Studies ◽  
Energy Calculation

AbstractThe recent dissemination of SARS-CoV-2 from Wuhan city to all over the world has created a pandemic. COVID-19 has cost many human lives and created an enormous economic burden. Although many drugs/vaccines are in different stages of clinical trials, still none is clinically available. We have screened a marine seaweed database (1110 compounds) against 3CLpro of SARS-CoV-2 using computational approaches. High throughput virtual screening was performed on compounds, and 86 of them with docking score <  − 5.000 kcal mol−1 were subjected to standard-precision docking. Based on binding energies (< − 6.000 kcal mol−1), 9 compounds were further shortlisted and subjected to extra-precision docking. Free energy calculation by Prime-MM/GBSA suggested RC002, GA004, and GA006 as the most potent inhibitors of 3CLpro. An analysis of ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of RC002, GA004, and GA006 indicated that only RC002 (callophysin A, from red alga Callophycus oppositifolius) passed Lipinski’s, Veber’s, PAINS and Brenk’s filters and displayed drug-like and lead-like properties. Analysis of 3CLpro-callophysin A complex revealed the involvement of salt bridge, hydrogen bonds, and hydrophobic interactions. callophysin A interacted with the catalytic residues (His41 and Cys145) of 3CLpro; hence it may act as a mechanism-based competitive inhibitor. Docking energy and docking affinity of callophysin A towards 3CLpro was − 8.776 kcal mol−1 and 2.73 × 106 M−1, respectively. Molecular dynamics simulation confirmed the stability of the 3CLpro-callophysin A complex. The findings of this study may serve as the basis for further validation by in vitro and in vivo studies.

MR-GUIDED PULSE OXIMETRY IMAGING OF BREAST IN VIVO

2011 ◽  
Vol 04 (02) ◽  
pp. 199-208
Author(s):  
ZHIQIU LI ◽  
SHUDONG JIANG ◽  
VENKATARAMANAN KRISHNASWAMY ◽  
SCOTT C. DAVIS ◽  
SUBHADRA SRINIVASAN ◽  
...  
Keyword(s):  
Breast Tissue ◽  
Near Infrared ◽  
Imaging System ◽  
Structural Information ◽  
Human Subjects ◽  
Nir Spectroscopy ◽  
Tomography System ◽  
Finger Pulse ◽  
Lock In

A near-infrared (NIR) tomography system with spectrally-encoded sources in two wavelength bands was built to quantify the temporal oxyhemoglobin and deoxyhemoglobin contrast in breast tissue at a 20 Hz bandwidth. The system was integrated into a 3 T magnetic resonance (MR) imaging system through a customized breast coil interface for simultaneous optical and MRI acquisition. In this configuration, the MR images provide breast tissue structural information for NIR spectroscopy of adipose and fibro-glandular tissue in breast. Spectral characterization performance of the NIR system was verified through dynamic phantom experiments. Normal human subjects were imaged with finger pulse oximeter (PO) plethysmogram synchronized to the NIR system to provide a frequency-locked reference. Both the raw data from the NIR system and the recovered absorption coefficients of the breast at two wavelengths showed the same frequency of about 1.3 Hz as the PO output. The frequency lock-in approach provided a practical platform for MR-localized recovery of small pulsatile variations of oxyhemoglobin and deoxyhemoglobin in the breast, which are related to the heartbeat and vascular resistance of the tissue.

Sign in / Sign up

Export Citation Format

Share Document