In recent decades, the excellent properties of rare-earth doped nanoparticles (RENPs), such as multiple optical properties, high photostability, long lifetime, and low cytotoxicity, have made them... Show moreIn recent decades, the excellent properties of rare-earth doped nanoparticles (RENPs), such as multiple optical properties, high photostability, long lifetime, and low cytotoxicity, have made them one of the main research trends for optical probes. Their promising applications in the biomedical field have further contributed to this trend.This thesis focuses on two aspects of RENPs as biological carriers and multifunctional imaging probes for disease therapy and diagnosis. Firstly, we investigated the effectiveness of a nanoplatform constructed with upconversion nanoparticles (UCNPs) as a carrier for immunotherapy due to the modifiability and high luminescence efficiency of UCNPs. This approach successfully achieved an immunotherapeutic strategy that could be tracked in real time.Secondly, as single imaging modality probes are time-consuming and have low diagnostic efficiency in disease diagnosis, we synthesized and optimized RENPs with multifunctional imaging capabilities using specific ions in their compositions, and we also performed preliminary evaluations of various imaging properties. Our findings provide a viable idea for reducing healthcare costs and improving healthcare efficiency. Show less
Ke, M.; Feng, L.; Huang, S.; Lu, T.; Yu, Z.; Yang, Y.; ... ; Qian, H. 2022
Harmful cyanobacterial blooms (HCBs) caused by Microcystis aeruginosa are of great concern as they negatively affect the aquatic environment and human health. Chemical methods could rapidly... Show moreHarmful cyanobacterial blooms (HCBs) caused by Microcystis aeruginosa are of great concern as they negatively affect the aquatic environment and human health. Chemical methods could rapidly eradicate HCBs and have been used for many decades. However, many chemical reagents are not recommended to eliminate HCBs in the long term, given the possible destructive and toxic effects of the chemicals employed on non-target aquatic organisms. We developed a new algaecide, 2-((1,3,4-thiadiazol-2-yl)thio)-N-(4-chlorophenyl) acetamide (Q2), to control harmful cyanobacteria while being environmentally friendly and selective. In our study, Q2 effectively inhibited cyanobacterial growth, especially of M. aeruginosa, but did not affect eukaryotic algae in test concentrations. A critical mechanism was revealed by transcriptome and metagenomic results showing that Q2 affects multiple cellular targets of cyanobacteria for HCB control, including the destruction of organelles, damage in the photosynthesis center, as well as inhibition of gas vesicle growth, and these changes can be highly relevant to the decrease of quorum-sensing functional KEGG pathways. Furthermore, Q2 did not affect the microbial composition and could recover the disrupted aquatic functional pathways in a short period. This is different from the impact on ecosystem functioning of the traditionally used harmful algaecide diuron. All these results verified that Q2 could be friendly to the aquatic environment, providing a new directional choice in managing HCBs in the future. Show less
Due to its effectivity and efficiency, deep hashing approaches are widely used for large-scale visual search. However, it is still challenging to produce compact and discriminative hash codes for... Show moreDue to its effectivity and efficiency, deep hashing approaches are widely used for large-scale visual search. However, it is still challenging to produce compact and discriminative hash codes for images asso-ciated with multiple semantics for two main reasons, 1) similarity constraints designed in most of the existing methods are based upon an oversimplified similarity assignment (i.e., 0 for instance pairs sharing no label, 1 for instance pairs sharing at least 1 label), 2) the exploration in multi-semantic relevance are insufficient or even neglected in many of the existing methods. These problems significantly limit the dis-crimination of generated hash codes. In this paper, we propose a novel Deep Hashing with Self-Supervised Asymmetric Semantic Excavation and Margin-Scalable Constraint(SADH) approach to cope with these problems. SADH implements a self-supervised network to sufficiently preserve semantic information in a semantic feature dictionary and a semantic code dictionary for the semantics of the given dataset, which efficiently and precisely guides a feature learning network to preserve multi-label semantic information using an asymmetric learning strategy. By further exploiting semantic dictionaries, a new margin-scalable constraint is employed for both precise similarity searching and robust hash code generation. Extensive empirical research on four popular benchmarks validates the proposed method and shows it outperforms several state-of-the-art approaches. The source codes URL of our SADH is: http:// github.com/SWU-CS-MediaLab/SADH. (c) 2022 Elsevier B.V. All rights reserved. Show less
Tin, A.; Marten, J.; Kuhns, V.L.H.; Li, Y.; Wuttke, M.; Kirsten, H.; ... ; VA Million Vet Program 2019
Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in... Show moreElevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits. Show less
Teumer, A.; Li, Y.; Ghasemi, S.; Prins, B.P.; Wuttke, M.; Hermle, T.; ... ; Kottgen, A. 2019
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are... Show moreIncreased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n =192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria. Show less
Wuttke, M.; Li, Y.; Li, M.; Sieber, K.B.; Feitosa, M.F.; Gorski, M.; ... ; Waterwort 2019
This paper provides an overview of the discussion and presentations from the Workshop on the Management of Large CryoEM Facilities held at the New York Structural Biology Center, New York, NY on... Show moreThis paper provides an overview of the discussion and presentations from the Workshop on the Management of Large CryoEM Facilities held at the New York Structural Biology Center, New York, NY on February 6-7, 2017. A major objective of the workshop was to discuss best practices for managing cryoEM facilities. The discussions were largely focused on supporting single-particle methods for cryoEM and topics included: user access, assessing projects, workflow, sample handling, microscopy, data management and processing, and user training. Show less
Sala, L.; Yu, Z.; Ward-van Oostwaard, D.; Veldhoven, J.P.D. van; Moretti, A.; Laugwitz, K.L.; ... ; Bellin, M. 2016
BACKGROUND: Ventricular arrhythmias as a result of unintentional blockade of the Kv11.1 (hERG [human ether-à-go-go-related gene]) channel are a major safety concern in drug development. In past... Show moreBACKGROUND: Ventricular arrhythmias as a result of unintentional blockade of the Kv11.1 (hERG [human ether-à-go-go-related gene]) channel are a major safety concern in drug development. In past years, several highly prescribed drugs have been withdrawn for their ability to cause such proarrhythmia. Here, we investigated whether the proarrhythmic risk of existing drugs could be reduced by Kv11.1 allosteric modulators.METHODS AND RESULTS: Using [(3)H]dofetilide-binding assays with membranes of human Kv11.1-expressing human embryonic kidney 293 cells, 2 existing compounds (VU0405601 and ML-T531) and a newly synthesized compound (LUF7244) were found to be negative allosteric modulators of dofetilide binding to the Kv11.1 channel, with LUF7244 showing the strongest effect at 10 μmol/L. The Kv11.1 affinities of typical blockers (ie, dofetilide, astemizole, sertindole, and cisapride) were significantly decreased by LUF7244. Treatment of confluent neonatal rat ventricular myocyte (NRVM) monolayers with astemizole or sertindole caused heterogeneous prolongation of action potential duration and a high incidence of early afterdepolarizations on 1-Hz electric point stimulation, occasionally leading to unstable, self-terminating tachyarrhythmias. Pretreatment of NRVMs with LUF7244 prevented these proarrhythmic effects. NRVM monolayers treated with LUF7244 alone displayed electrophysiological properties indistinguishable from those of untreated NRVM cultures. Prolonged exposure of NRVMs to LUF7244 or LUF7244 plus astemizole did not affect their viability, excitability, and contractility as assessed by molecular, immunological, and electrophysiological assays.CONCLUSIONS: Allosteric modulation of the Kv11.1 channel efficiently suppresses drug-induced ventricular arrhythmias in vitro by preventing potentially arrhythmogenic changes in action potential characteristics, raising the possibility to resume the clinical use of unintended Kv11.1 blockers via pharmacological combination therapy.KEYWORDS: arrhythmias, cardiac; cardiotoxicity; cell culture techniques; myocytes, cardiac; potassium voltage-gated channel, subfamily H, member 2; radioligand assay; voltage-sensitive dye imaging Show less
We synthesized and evaluated a series of compounds for their allosteric modulation at the Kv11.1 (hERG) channel. Most compounds were negative allosteric modulators of [(3)H]dofetilide binding to... Show moreWe synthesized and evaluated a series of compounds for their allosteric modulation at the Kv11.1 (hERG) channel. Most compounds were negative allosteric modulators of [(3)H]dofetilide binding to the channel, in particular 7f, 7h-j and 7p. Compounds 7f and 7p were the most potent negative allosteric modulators amongst all ligands, significantly increasing the dissociation rate of dofetilide in the radioligand kinetic binding assay, while remarkably reducing the affinities of dofetilide and astemizole in a competitive displacement assay. Additionally, both 7f and 7p displayed peculiar displacement characteristics with Hill coefficients significantly distinct from unity as shown by e.g., dofetilide, further indicative of their allosteric effects on dofetilide binding. Our findings in this investigation yielded several promising negative allosteric modulators for future functional and clinical research with respect to their antiarrhythmic propensities, either alone or in combination with known Kv11.1 blockers. Show less
Kv11.1-induced cardiotoxicity has emerged as an unanticipated adverse effect of many pharmacological agents and has become a major obstacle in drug development over the past decades. In this thesis... Show moreKv11.1-induced cardiotoxicity has emerged as an unanticipated adverse effect of many pharmacological agents and has become a major obstacle in drug development over the past decades. In this thesis, allosteric modulation of the Kv11.1 channel has been extensively explored, and negative allosteric modulators were shown to relieve the proarrhythmic effects of structurally and therapeutically diverse Kv11.1 blockers. The most potent modulators may be developed as a new class of antiarrhythmic medications in the future. On the other hand, kinetic binding parameters of a wide range of Kv11.1 blockers at the channel have been thoroughly investigated in this thesis. Association and dissociation rates or residence times are strongly suggested to be integrated with equilibrium affinity values into the future paradigms for a better and more comprehensive evaluation of Kv11.1 liability of drug candidates. The __kon-koff-KD__ kinetic map provides a first and promising classification of Kv11.1 blockers, which could be beneficial and indicative for drug researchers to design compounds with less Kv11.1-mediated cardiac side effects in the early stage of drug development. Hopefully, all findings in this thesis have brought new insights into Kv11.1-induced cardiac arrhythmias, and will offer opportunities for restoring or preventing this kind of arrhythmias in the near future. Show less
Vilums, M.; Zweemer, A.J.; Barmare, F.; Gracht, A.M. van der; Bleeker, D.C.T.; Yu, Z.; ... ; IJzerman, A.P. 2015
Chemokine ligand 2 (CCL2) mediates chemotaxis of monocytes to inflammatory sites via interaction with its G protein-coupled receptor CCR2. Preclinical animal models suggest that the CCL2-CCR2 axis... Show moreChemokine ligand 2 (CCL2) mediates chemotaxis of monocytes to inflammatory sites via interaction with its G protein-coupled receptor CCR2. Preclinical animal models suggest that the CCL2-CCR2 axis has a critical role in the development and maintenance of inflammatory disease states (e.g., multiple sclerosis, atherosclerosis, insulin resistance, restenosis, and neuropathic pain), which can be treated through inhibition of the CCR2 receptor. However, in clinical trials high-affinity inhibitors of CCR2 have often demonstrated a lack of efficacy. We have previously described a new approach for the design of high-affinity CCR2 antagonists, by taking their residence time (RT) on the receptor into account. Here, we report our findings on both structure-affinity relationship (SAR) and structure-kinetic relationship (SKR) studies for a series of 3-((inden-1-yl)amino)-1-isopropyl-cyclopentane-1-carboxamides as CCR2 antagonists. SAR studies showed that this class of compounds tolerates a vast diversity of substituents on the indenyl ring with only small changes in affinity. However, the SKR is affected greatly by minor modifications of the structure. The combination of SAR and SKR in the hit-to-lead process resulted in the discovery of a new high-affinity and long-residence-time CCR2 antagonist (compound 15a, Ki = 2.4 nM; RT = 714 min). Show less
BACKGROUND AND PURPOSE\nDrug-induced arrhythmia due to blockade of the Kv 11.1 channel (also known as the hERG K(+) channel) is a frequent side effect. Previous studies have primarily focused on... Show moreBACKGROUND AND PURPOSE\nDrug-induced arrhythmia due to blockade of the Kv 11.1 channel (also known as the hERG K(+) channel) is a frequent side effect. Previous studies have primarily focused on equilibrium parameters, i.e. affinity or potency, of drug candidates at the channel. The aim of this study was to determine the kinetics of the interaction with the channel for a number of known Kv 11.1 blockers and to explore a possible correlation with the affinity or physicochemical properties of these compounds.\nEXPERIMENTAL APPROACH\nThe affinity and kinetic parameters of 15 prototypical Kv 11.1 inhibitors were evaluated in a number of [(3) H]-dofetilide binding assays. The lipophilicity (logKW - C8 ) and membrane partitioning (logKW - IAM ) of these compounds were determined by means of HPLC analysis.\nKEY RESULTS\nA novel [(3) H]-dofetilide competition association assay was set up and validated, which allowed us to determine the binding kinetics of the Kv 11.1 blockers used in this study. Interestingly, the compounds' affinities (Ki values) were correlated to their association rates rather than dissociation rates. Overall lipophilicity or membrane partitioning of the compounds were not correlated to their affinity or rate constants for the channel.\nCONCLUSIONS AND IMPLICATIONS\nA compound's affinity for the Kv 11.1 channel is determined by its rate of association with the channel, while overall lipophilicity and membrane affinity are not. In more general terms, our findings provide novel insights into the mechanism of action for a compound's activity at the Kv 11.1 channel. This may help to elucidate how Kv 11.1-induced cardiotoxicity is governed and how it can be circumvented in the future. Show less
