Hepatotoxicity is the most frequent reason for the withdrawal of an approved drug from the market. Monolayer culture of hepatocyte in two-dimension, which is relatively inexpensive, convenient and ...easy to use, serves a traditional hepatocyte-based high-content screening for identifying hepatotoxic side effects of tested drugs. However, two-dimensional methods have their limitations in lack of insensitivity on reflection of drug hepatotoxicity. Three-dimensional (3D) cultures of hepatocytes in sandwich, spheroid and gel entrapment provide a microenvironment for high expression of liver-specific functions and are being proposed for prediction of drug hepatotoxicity.
This review addressed the reliability of 3D culture models on screening hepatotoxic drugs with particular emphasis on gel entrapment culture model due to its more systematic data on drug testing.
The reader will gain a comprehensive understanding of the improved prediction efficacy of 3D culture models.
Hepatocytes in 3D cultures, although in need of further standardization required by the throughput operation, show great potential in attempts to ensure the efficacy on prediction of drug hepatotoxicity.
Fast and strong bio-adhesives are in high demand for many biomedical applications, including closing wounds in surgeries, fixing implantable devices, and haemostasis. However, most strong ...bio-adhesives rely on the instant formation of irreversible covalent crosslinks to provide strong surface binding. Repositioning misplaced adhesives during surgical operations may cause severe secondary damage to tissues. Here, we report hydrogel tapes that can form strong physical interactions with tissues in seconds and gradually form covalent bonds in hours. This timescale-dependent adhesion mechanism allows instant and robust wet adhesion to be combined with fault-tolerant convenient surgical operations. Specifically, inspired by the catechol chemistry discovered in mussel foot proteins, we develop an electrical oxidation approach to controllably oxidize catechol to catecholquinone, which reacts slowly with amino groups on the tissue surface. We demonstrate that the tapes show fast and reversible adhesion at the initial stage and ultrastrong adhesion after the formation of covalent linkages over hours for various tissues and electronic devices. Given that the hydrogel tapes are biocompatible, easy to use, and robust for bio-adhesion, we anticipate that they may find broad biomedical and clinical applications.
Nanozyme‐based tumor catalytic therapy has attracted widespread attention in recent years. However, its therapeutic outcomes are diminished by many factors in the tumor microenvironment (TME), such ...as insufficient endogenous hydrogen peroxide (H2O2) concentration, hypoxia, and immunosuppressive microenvironment. Herein, an immunomodulation‐enhanced nanozyme‐based tumor catalytic therapy strategy is first proposed to achieve the synergism between nanozymes and TME regulation. TGF‐β inhibitor (TI)‐loaded PEGylated iron manganese silicate nanoparticles (IMSN) (named as IMSN‐PEG‐TI) are constructed to trigger the therapeutic modality. The results show that IMSN nanozyme exhibits both intrinsic peroxidase‐like and catalase‐like activities under acidic TME, which can decompose H2O2 into hydroxyl radicals (•OH) and oxygen (O2), respectively. Besides, it is demonstrated that both IMSN and TI can regulate the tumor immune microenvironment, resulting in macrophage polarization from M2 to M1, and thus inducing the regeneration of H2O2, which can promote catalytic activities of IMSN nanozyme. The potent antitumor effect of IMSN‐PEG‐TI is proved by in vitro multicellular tumor spheroids (MCTS) and in vivo CT26‐tumor‐bearing mice models. It is believed that the immunomodulation‐enhanced nanozyme‐based tumor treatment strategy is a promising tool to kill cancer cells.
An immunomodulation‐enhanced nanozyme‐based tumor catalytic treatment strategy is developed to fight against cancer. By regulating the tumor immune microenvironment, an increased generation level of hydrogen peroxide is demonstrated, thus effectively improving the catalytic activities of iron manganese silicate nanoparticle nanozymes. As a result, a high tumor therapeutic effect with a tumor inhibition rate of 87.5% is achieved.
Summary
Lignified stone cells substantially reduce fruit quality. Therefore, it is desirable to inhibit stone cell development using genetic technologies. However, the molecular mechanisms regulating ...lignification are poorly understood in fruit stone cells. In this study, we have shown that microRNA (miR) miR397a regulates fruit cell lignification by inhibiting laccase (LAC) genes that encode key lignin biosynthesis enzymes. Transient overexpression of PbrmiR397a, which is the miR397a of Chinese pear (Pyrus bretschneideri), and simultaneous silencing of three LAC genes reduced the lignin content and stone cell number in pear fruit. A single nucleotide polymorphism (SNP) identified in the promoter of the PbrmiR397a gene was found to associate with low levels of fruit lignin, after analysis of the genome sequences of sixty pear varieties. This SNP created a TCA element that responded to salicylic acid to induce gene expression as confirmed using a cell‐based assay system. Furthermore, stable overexpression of PbrmiR397a in transgenic tobacco plants reduced the expression of target LAC genes and decreased the content of lignin but did not change the ratio of syringyl‐ and guaiacyl‐lignin monomers. Consistent with reduction in lignin content, the transgenic plants showed fewer numbers of vessel elements and thinner secondary walls in the remaining elements compared to wild‐type control plants. This study has advanced our understanding of the regulation of lignin biosynthesis and provided useful molecular genetic information for improving pear fruit quality.
Hydrogel-based devices are widely used as flexible electronics, biosensors, soft robots, and intelligent human-machine interfaces. In these applications, high stretchability, low hysteresis, and ...anti-fatigue fracture are essential but can be rarely met in the same hydrogels simultaneously. Here, we demonstrate a hydrogel design using tandem-repeat proteins as the cross-linkers and random coiled polymers as the percolating network. Such a design allows the polyprotein cross-linkers only to experience considerable forces at the fracture zone and unfold to prevent crack propagation. Thus, we are able to decouple the hysteresis-toughness correlation and create hydrogels of high stretchability (~1100%), low hysteresis (< 5%), and high fracture toughness (~900 J m
). Moreover, the hydrogels show a high fatigue threshold of ~126 J m
and can undergo 5000 load-unload cycles up to 500% strain without noticeable mechanical changes. Our study provides a general route to decouple network elasticity and local mechanical response in synthetic hydrogels.
Developing ultrasensitive chemical sensors with small scale and fast response through simple design and low‐cost fabrication is highly desired but still challenging. Herein, a simple and universal ...sensing platform based on a hydrogel interferometer with femtomol‐level sensitivity in detecting (bio)chemical molecules is demonstrated. A unique local concentrating effect (up to 109 folds) in the hydrogel induced by the strong analyte binding and large amount of ligands, combined with the signal amplification effect by optical interference, endows this platform with an ultrahigh sensitivity, specifically 10−14m for copper ions and 1.0 × 10−11 mg mL−1 for glycoprotein with 2–4 order‐of‐magnitude enhancement. The specific chemical reactions between selected ligands and target analytes provide high selectivity in detecting complex fluids. This universal principle with broad chemistry, simple physics, and modular design allows for high performance in detecting wide customer choices of analytes, including metal ions and proteins. The scale of the sensor can be down to micrometer size. The nature of the soft gel makes this platform transparent, flexible, stretchable, and compatible with a variety of substrates, showing high sensing stability and robustness after 200 cycles of bending or stretching. The outstanding sensing performance grants this platform great promise in broad practical applications.
A universal sensing platform with highly sensitive and selective chemical detection based on hydrogel interferometry is introduced. The sensitivity reaches a femtomol‐level record‐low detection limit, 102–104 orders of magnitude higher than the pre‐existing methods. The selectivity can be on‐demand specified through selected chemical reaction. The general platform further enables optical transparency, mechanical stretchability, and mechanical durability.
Hydrogels are known to have the advantages such as good biodegradability, biocompatibility, and easy functionalization, making them ideal candidates for biosensors. Hydrogel‐based biosensors that ...respond to bacteria‐induced microenvironmental changes such as pH, enzymes, antigens, etc., or directly interact with bacterial surface receptors, can be applied for early diagnosis of bacterial infections, providing information for timely treatment while avoiding antibiotic abuse. Furthermore, hydrogel biosensors capable of both bacteria diagnosis and treatment will greatly facilitate the development of point‐of‐care monitoring of bacterial infections. In this review, the recent advancement of hydrogel‐based biosensors for bacterial infection is summarized and discussed. First, the biosensors based on pH‐sensitive hydrogels, bacterial‐specific secretions‐sensitive hydrogels, and hydrogels directly in contact with bacterial surfaces are presented. Next, hydrogel biosensors capable of detecting bacterial infection in the early stage followed by immediate on‐demand treatment are discussed. Finally, the challenges and future development of hydrogel biosensors for bacterial infections are proposed.
Hydrogels possess many advantageous properties, including a high‐water content, large specific surface area, excellent biocompatibility, easy functionalization, and unique stimuli‐responsive characteristics, making them highly promising materials for bacterial sensing. This review provides an overview and discussion of the recent progress made in hydrogel‐based biosensors for the detection of bacterial infections and bacterial theranostics.
•Bootstrap full- and sub-sample rolling-window Granger causality tests are applied.•Bitcoin and oil cannot always be in the same boat.•The burst of the Bitcoin bubble has weakened the hedging ability ...of Bitcoin.•The demand for oil to invest may be threatened by the increasing Bitcoin price.•Investors and governments can benefit from this investigation to optimize their investment and ensure the stable development of Bitcoin and oil markets.
Bitcoin and the blockchain technology on which it is based are the key drivers behind the accelerated pace of Fourth Industrial Revolution in the domain of Finance. The offshoots of this technology however are not limited and are rapidly spreading in other domains such as oil market. This paper investigates the causality or influences that both markets, Bitcoin price (BP) and oil price (OP) have on each other by applying the bootstrap Granger causal relationship tests considering full as well as sub-samples. Our analysis reveals that shocks originated in OP and transmitted towards BP can be both positive or negative. The positive impact indicates that Bitcoin can be viewed as an asset helpful in avoiding the risks of the high OP, which also indicates that Bitcoin and oil are in the same boat, however, the negative effects cannot support this view. The negative influence of OP on BP can be explained by the burst of the Bitcoin bubble which has weakened its hedging ability. In turn, there is also a negative influence or reverse causality running from BP to OP, highlighting that the demand for oil by investors can be threatened by the increasing BP. Keeping in view the more integrated and complexed financial dynamics which are the results of Fourth Industrial Revolution, investors can benefit from this interrelationship to diversify the risks and optimize their investment by building a more balanced portfolio. Also, governments could promote and protect the healthy development of the Bitcoin and energy market by preventing the Bitcoin bubbles and understanding the reasons of oil price volatility.
•Cold-tolerant anammox was acclimated successfully with temperature change.•Adverse effects caused by low temperature (8 °C) could be restored.•SAA of anammox acclimated at 23 °C on ex situ ...temperature (33 and 28 °C) was higher.•Ca. Kuenenia was more abundant (55.18%) in the microbial community at 13 °C.
A lab-scale anammox up-flow anaerobic sludge blanket (UASB) reactor was run to investigate the influence of temperature on anammox performance and community structure. The anammox system had a higher substrate tolerance at 13 °C than at 18 °C. The adverse effects caused by the use of a lower temperature (8 °C) could be restored. The nitrogen removal rate (NRR) decreased with decreasing in situ specific anammox activity (SAA). Interestingly, the ex situ SAA acclimated at 23 °C, when exposed to ex situ temperatures of 33 and 28 °C, was higher than for those acclimated at 33 and 28 °C. No shift was observed in the optimum temperature for ex situ SAA in the whole lowering process of anammox UASB. More extracellular polymeric substances were produced in response to cooler conditions (18 °C and 13 °C). Ca. Kuenenia became much more abundant (55.18% of the microbial community) and had a competitive advantage over other anammox bacteria (AnAOB) at 13 °C.
Protein folding guides disulfide bond formation Qin, Meng; Wang, Wei; Thirumalai, D.
Proceedings of the National Academy of Sciences - PNAS,
09/2015, Letnik:
112, Številka:
36
Journal Article
Recenzirano
Odprti dostop
The Anfinsen principle that the protein sequence uniquely determines its structure is based on experiments on oxidative refolding of a protein with disulfide bonds. The problem of how protein folding ...drives disulfide bond formation is poorly understood. Here, we have solved this long-standing problem by creating a general method for implementing the chemistry of disulfide bond formation and rupture in coarse-grained molecular simulations. As a case study, we investigate the oxidative folding of bovine pancreatic trypsin inhibitor (BPTI). After confirming the experimental findings that the multiple routes to the folded state contain a network of states dominated by native disulfides, we show that the entropically unfavorable native single disulfide 14–38 between Cys14and Cys38forms only after polypeptide chain collapse and complete structuring of the central core of the protein containing an antiparallel β-sheet. Subsequent assembly, resulting in native two-disulfide bonds and the folded state, involves substantial unfolding of the protein and transient population of nonnative structures. The rate of 14–38 formation increases as the β-sheet stability increases. The flux to the native state, through a network of kinetically connected native-like intermediates, changes dramatically by altering the redox conditions. Disulfide bond formation between Cys residues not present in the native state are relevant only on the time scale of collapse of BPTI. The finding that formation of specific collapsed native-like structures guides efficient folding is applicable to a broad class of single-domain proteins, including enzyme-catalyzed disulfide proteins.
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