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The continuously increasing level of atmospheric CO2 in the atmosphere has led to global warming. Converting CO2 into other carbon compounds could mitigate its atmospheric levels and produce valuable products, as CO2 also serves as a plentiful and inexpensive carbon feedstock. However, the inert nature of CO2 poses a major challenge for its reduction. To meet the challenge, nature has evolved metalloenzymes using transition metal ions like Fe, Ni, Mo, and W, as well as electron-transfer partners for their functions. Mimicking these enzymes, artificial metalloenzymes (ArMs) have been designed using alternative protein scaffolds and various metallocofactors like Ni, Co, Re, Rh, and FeS clusters. Both the catalytic efficiency and the scope of CO2-reduction product of these ArMs have been improved over the past decade. This review first focuses on the natural metalloenzymes that directly reduce CO2 by discussing their structures and active sites, as well as the proposed reaction mechanisms. It then introduces the common strategies for electrochemical, photochemical, or photoelectrochemical utilization of these native enzymes for CO2 reduction and highlights the most recent advancements from the past five years. We also summarize principles of protein design for bio-inspired ArMs, comparing them with native enzymatic systems and outlining challenges and opportunities in enzymatic CO2 reduction.
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Dióxido de Carbono , Metaloproteínas , Oxidación-Reducción , Dióxido de Carbono/química , Dióxido de Carbono/metabolismo , Metaloproteínas/química , Metaloproteínas/metabolismo , Catálisis , Biocatálisis , Dominio CatalíticoRESUMEN
Organic light-emitting diodes (OLEDs) that are able to emit high levels of circularly polarized (CP) light hold significant promise in numerous future technologies. Such devices require chiral emissive materials to enable CP electroluminescence. However, the vast majority of current OLED emitter classes, including the state-of-the-art triplet-harvesting thermally activated delayed fluorescence (TADF) materials, produce very low levels of CP electroluminescence. Here a host-guest strategy that allows for energy transfer between a chiral polymer host and a representative chiral TADF emitter is showcased. Such a mechanism results in a large amplification of the circular polarization of the emitter. As such, this study presents a promising avenue to further boost the performance of circularly polarized organic light-emitting diode devices, enabling their further development and eventual commercialization.
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Stretchable flexible strain sensors based on conductive elastomers are rapidly emerging as a highly promising candidate for popular wearable flexible electronic and soft-mechanical sensing devices. However, due to the intrinsic limitations of low fidelity and high hysteresis, existing flexible strain sensors are unable to exploit their full application potential. Herein, a design strategy for a successive three-dimensional crack conductive network is proposed to cope with the uncoordinated variation of the output resistance signal arising from the conductive elastomer. The electrical characteristics of the sensor are dominated by the successive crack conductive network through a greater resistance variation and a concise sensing mechanism. As a result, the developed elastomer bionic strain sensors exhibit excellent sensing performance in terms of a smaller overshoot response, a lower hysteresis (â¼2.9%), and an ultralow detection limit (0.00179%). What's more, the proposed strategy is universal and applicable to many conductive elastomers with different conductive fillers (including 0-D, 1-D, and 2-D conductive fillers). This approach improves the sensing signal accuracy and reliability of conductive elastomer strain sensors and holds promising potential for various applications in the fields of e-skin and soft robotic systems.
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The key to type 1 copper (T1Cu) function lies in the fine tuning of the CuII/I reduction potential (E°'T1Cu ) to match those of its redox partners, enabling efficient electron transfer in a wide range of biological systems. While the secondary coordination sphere (SCS) effects have been used to tune E°'T1Cu in azurin over a wide range, these principles are yet to be generalized to other T1Cu-containing proteins to tune catalytic properties. To this end, we have examined the effects of Y229F, V290N and S292F mutations around the T1Cu of small laccase (SLAC) from Streptomyces coelicolor to match the high E°'T1Cu of fungal laccases. Using ultraviolet-visible absorption and electron paramagnetic resonance spectroscopies, together with X-ray crystallography and redox titrations, we have probed the influence of SCS mutations on the T1Cu and corresponding E°'T1Cu . While minimal and small E°'T1Cu increases are observed in Y229F- and S292F-SLAC, the V290N mutant exhibits a major E°'T1Cu increase. Moreover, the influence of these mutations on E°'T1Cu is additive, culminating in a triple mutant Y229F/V290N/S292F-SLAC with the highest E°'T1Cu of 556â mV vs. SHE reported to date. Further activity assays indicate that all mutants retain oxygen reduction reaction activity, and display improved catalytic efficiencies (kcat /KM ) relative to WT-SLAC.
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Lacasa , Streptomyces coelicolor , Cobre/química , Lacasa/metabolismo , Mutación , Oxidación-Reducción , Streptomyces coelicolor/genética , Streptomyces coelicolor/metabolismoRESUMEN
Multiresonant thermally activated delayed fluorescence (MR-TADF) compounds are attractive as emitters for organic light-emitting diodes (OLEDs) as they can simultaneously harvest both singlet and triplet excitons to produce light in the device and show very narrow emission spectra, which translates to excellent color purity. Here, we report the first example of an MR-TADF emitter (DOBDiKTa) that fuses together fragments from the two major classes of MR-TADF compounds, those containing boron (DOBNA) and those containing carbonyl groups (DiKTa) as acceptor fragments in the MR-TADF skeleton. The resulting molecular design, this compound shows desirable narrowband pure blue emission and efficient TADF character. The co-host OLED with DOBDiKTa as the emitter showed a maximum external quantum efficiency (EQEmax ) of 17.4 %, an efficiency roll-off of 32 % at 100â cd m-2 , and Commission Internationale de l'Éclairage (CIE) coordinates of (0.14, 0.12). Compared to DOBNA and DiKTa, DOBDiKTa shows higher device efficiency with reduced efficiency roll-off while maintaining a high color purity, which demonstrates the promise of the proposed molecular design.
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Bioconjugation, a synthetic tool that endows small molecules with biocompatibility and target specificity through covalent attachment of a biomolecule, holds promise for next-generation diagnosis or therapy. Besides the establishment of chemical bonding, such chemical modification concurrently allows alteration of the physicochemical properties of small molecules, but this has been paid less attention in designing novel bioconjugates. Here, we report a "two birds one stone" methodology for irreversible porphyrin bioconjugation based on ß-fluoropyrrolyl-cysteine SNAr chemistry, in which the ß-fluorine of porphyrin is selectively replaced by a cysteine in either peptides or proteins to generate novel ß-peptidyl/proteic porphyrins. Notably, due to the distinct electronic nature between fluorine and sulfur, such replacement makes the Q band red-shift to the near-infrared region (NIR, >700 nm). This facilitates intersystem crossing (ISC) to enhance the triplet population and thus singlet oxygen production. This new methodology features water tolerance, a fast reaction time (15 min), good chemo-selectivity, and broad substrate scope, including various peptides and proteins under mild conditions. To demonstrate its potential, we applied porphyrin ß-bioconjugates in several scenarios, including (1) cytosolic delivery of functional proteins, (2) metabolic glycan labeling, (3) caspase-3 detection, and (4) tumor-targeting phototheranostics.
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Resistance to anoikis is a key characteristic of many cancer cells, promoting cell survival. However, the mechanism of anoikis in hepatocellular carcinoma (HCC) remains unknown. In this study, we applied differentially expressed overlapping anoikis-related genes to classify The Cancer Genome Atlas (TCGA) samples using an unsupervised cluster algorithm. Then, we employed weighted gene coexpression network analysis (WGCNA) to identify highly correlated genes and constructed a prognostic risk model based on univariate Cox proportional hazards regression. This model was validated using external datasets from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). Finally, we used a CIBERSORT algorithm to investigate the correlation between risk score and immune infiltration. Our results showed that the TCGA cohorts could be divided into two subgroups, with subgroup A having a lower survival probability. Five genes (BAK1, SPP1, BSG, PBK and DAP3) were identified as anoikis-related prognostic genes. Moreover, the prognostic risk model effectively predicted overall survival, which was validated using ICGC and GEO datasets. In addition, there was a strong correlation between infiltrating immune cells and prognostic genes and risk score. In conclusion, we identified anoikis-related subgroups and prognostic genes in HCC, which could be significant for understanding the molecular mechanisms and treatment of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Anoicis/genética , Neoplasias Hepáticas/genética , AlgoritmosRESUMEN
Autophagy is a highly conserved cellular process that profoundly impacts the efficacy of genotoxic chemotherapeutic drugs. TGF-ß-activated kinase 1 (TAK1) is a serine/threonine kinase that activates several signaling pathways involved in inducing autophagy and suppressing cell death. Xanthine oxidoreductase (XOR) is a rate-limiting enzyme that converts hypoxanthine to xanthine, and xanthine to uric acid and hydrogen peroxide in the purine catabolism pathway. Recent studies showed that uric acid can bind to TAK1 and prolong its activation. We hypothesized that genotoxic drugs may induce autophagy and apoptosis resistance by activating TAK1 through XOR-generated uric acid. Here, we report that gemcitabine and 5-fluorouracil (5-FU), two genotoxic drugs, induced autophagy in HeLa and HT-29 cells by activating TAK1 and its two downstream kinases, AMP-activated kinase (AMPK) and c-Jun terminal kinase (JNK). XOR knockdown and the XOR inhibitor allopurinol blocked gemcitabine-induced TAK1, JNK, AMPK, and Unc51-like kinase 1 (ULK1)S555 phosphorylation and gemcitabine-induced autophagy. Inhibition of the ATM-Chk pathway, which inhibits genotoxic drug-induced uric acid production, blocked gemcitabine-induced autophagy by inhibiting TAK1 activation. Exogenous uric acid in its salt form, monosodium urate (MSU), induced autophagy by activating TAK1 and its downstream kinases JNK and AMPK. Gene knockdown or the inhibitors of these kinases blocked gemcitabine- and MSU-induced autophagy. Inhibition of autophagy by allopurinol, chloroquine, and 5Z-7-oxozeaenol (5Z), a TAK1-specific inhibitor, enhanced gemcitabine-induced apoptosis. Our study uncovers a previously unrecognized role of XOR in regulating genotoxic drug-induced autophagy and apoptosis and has implications for designing novel therapeutic strategies for cancer treatment.
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Ácido Úrico , Xantina Deshidrogenasa , Humanos , Ácido Úrico/farmacología , Ácido Úrico/metabolismo , Xantina Deshidrogenasa/genética , Xantina Deshidrogenasa/metabolismo , Alopurinol , Proteínas Quinasas Activadas por AMP/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Autofagia , Daño del ADN , ApoptosisRESUMEN
Flexible pressure sensors have provided an attractive option for potential applications in wearable fields like human motion monitoring or human-machine interfaces. For the development of flexible pressure sensors, achieving high performance or multifunctions are popular research tendencies in recent years, such as improving their sensitivity, working range, or stability. Sponge materials with porous structures have been demonstrated that they are one of the potential substrates for developing novel and excellent flexible pressure sensors. However, for sponge-based pressure sensors, it is still a great challenge to realize a wide range of pressures from Pa level to hundreds kPa level. And how to achieve mechanical robustness remains unsolved. Here, we develop a flexible pressure sensor based on multicarbon nanotubes (MWCNTs) network-coated porous elastomer sponge with a broad range and robust features for use in wearable applications. Specifically, polyurethane (PU) sponge is used as the substrate matrix while dip-coated PU/MWCNTs composites as a conductive layer, achieving a highly bonding effect between the substrate and the conductive material, hence a great mechanical robust advantage is obtained and the working range also is improved. The pressure sensor show range of up to 350 kPa, while the minimum detection threshold is as low as 150 Pa. And before and after rolling by a bicycle or electric motorcycle, the sensor has the almost same responses, exhibiting great robustness.
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Autophagy plays an important role in defending against invading microbes. However, numerous viruses can subvert autophagy to benefit their replication. Porcine epidemic diarrhoea virus (PEDV) is an aetiological agent that causes severe porcine epidemic diarrhoea. How PEDV infection regulates autophagy and its role in PEDV replication are inadequately understood. Herein, we report that PEDV induced complete autophagy in Vero and IPEC-DQ cells, as evidenced by increased LC3 lipidation, p62 degradation, and the formation of autolysosomes. The lysosomal protease inhibitors chloroquine (CQ) or bafilomycin A and Beclin-1 or ATG5 knockdown blocked autophagic flux and inhibited PEDV replication. PEDV infection activated AMP-activated protein kinase (AMPK) and c-Jun terminal kinase (JNK) by activating TGF-beta-activated kinase 1 (TAK1). Compound C (CC), an AMPK inhibitor, and SP600125, a JNK inhibitor, inhibited PEDV-induced autophagy and virus replication. AMPK activation led to increased ULK1S777 phosphorylation and activation. Inhibition of ULK1 activity by SBI-0206965 (SBI) and TAK1 activity by 5Z-7-Oxozeaenol (5Z) or by TAK1 siRNA led to the suppression of autophagy and virus replication. Our study provides mechanistic insights into PEDV-induced autophagy and how PEDV infection leads to JNK and AMPK activation.
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Virus de la Diarrea Epidémica Porcina , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Autofagia , Beclina-1 , Cloroquina , Quinasas Quinasa Quinasa PAM , Virus de la Diarrea Epidémica Porcina/fisiología , Inhibidores de Proteasas , ARN Interferente Pequeño , Porcinos , Replicación ViralRESUMEN
Metalloenzymes catalyze a variety of reactions using a limited number of natural amino acids and metallocofactors. Therefore, the environment beyond the primary coordination sphere must play an important role in both conferring and tuning their phenomenal catalytic properties, enabling active sites with otherwise similar primary coordination environments to perform a diverse array of biological functions. However, since the interactions beyond the primary coordination sphere are numerous and weak, it has been difficult to pinpoint structural features responsible for the tuning of activities of native enzymes. Designing artificial metalloenzymes (ArMs) offers an excellent basis to elucidate the roles of these interactions and to further develop practical biological catalysts. In this review, we highlight how the secondary coordination spheres of ArMs influence metal binding and catalysis, with particular focus on the use of native protein scaffolds as templates for the design of ArMs by either rational design aided by computational modeling, directed evolution, or a combination of both approaches. In describing successes in designing heme, nonheme Fe, and Cu metalloenzymes, heteronuclear metalloenzymes containing heme, and those ArMs containing other metal centers (including those with non-native metal ions and metallocofactors), we have summarized insights gained on how careful controls of the interactions in the secondary coordination sphere, including hydrophobic and hydrogen bonding interactions, allow the generation and tuning of these respective systems to approach, rival, and, in a few cases, exceed those of native enzymes. We have also provided an outlook on the remaining challenges in the field and future directions that will allow for a deeper understanding of the secondary coordination sphere a deeper understanding of the secondary coordintion sphere to be gained, and in turn to guide the design of a broader and more efficient variety of ArMs.
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Metaloproteínas , Catálisis , Dominio Catalítico , Hemo/química , Metaloproteínas/metabolismo , Metales/químicaRESUMEN
We describe herein a molecular design to generate circularly polarized thermally activated delayed fluorescence emitters in which chiral bicarbazole donors are connected to acceptor units via a rigid 8-membered cycle and how the nature of the donor and acceptor units affect the photophysical and chiroptical properties.
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Carbazoles/química , Colorantes , FluorescenciaRESUMEN
For advanced flexible strain sensors, it is not difficult to achieve high sensitivity only. However, integrating high sensitivity, high stability, and high durability into one sensor still remains a great challenge. Fortunately, natural creatures with diversified excellent performances have given us a lot of ready-made solutions. Here, scorpion and spiderweb are selected as coupling bionic prototypes, which are famous for their ultrasensitive sensing capacity and excellent structural durability, respectively. Based on that, a bioinspired strain sensor is successfully fabricated. The results demonstrate that the bioinspired strain sensor has a sensitivity of 940.5 in the strain range of 0-1.5% and a sensitivity of 2742.3 between 1.5 and 2.5%. Meantime, this sensor with a spiderweb-like reticular structure has a great improvement in stability and durability. Specifically, the sensor exhibits excellent stability during bending and stretching cycles over 80,000 times. Moreover, the response time and recovery time of the sensor are 169 and 195 ms, respectively. Besides, the sensor also has functions such as vibrating frequency identification due to its low hysteresis. Based on the excellent performance, the sensor can be applied to monitor human body motions serving as wearable electronics.
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Dispositivos Electrónicos Vestibles , Electrónica , Humanos , Monitoreo Fisiológico , Movimiento (Física)RESUMEN
DNA damage by genotoxic drugs such as gemcitabine and 5-fluorouracil (5-FU) activates the ataxia telangiectasia, mutated (ATM)-Chk pathway and induces the expression of NKG2D ligands such as the MHC class I-related chain A and B (MICA/B). The mechanisms underlying this remain incompletely understood. Here we report that xanthine oxidoreductase (XOR), a rate-limiting enzyme that produces uric acid in the purine catabolism pathway, promotes DNA damage-induced MICA/B expression. Inhibition of the ATM-Chk pathway blocks genotoxic drug-induced uric acid production, TGF-ß-activated kinase 1 (TAK1) activation, ERK phosphorylation, and MICA/B expression. Inhibition of uric acid production by the XOR inhibitor allopurinol blocks DNA damage-induced TAK1 activation and MICA/B expression in genotoxic drug-treated cells. Exogenous uric acid activates TAK1, NF-κB, and the MAP kinase pathway. TAK1 inhibition blocks gemcitabine- and uric acid-induced MAP kinase activation and MICA/B expression. Exogenous uric acid in its salt form, monosodium urate (MSU), induces MICA/B expression and sensitizes tumor cells to NK cell killing. MSU immunization with irradiated murine breast cancer cell line RCAS-Neu retards breast cancer growth in syngeneic breast cancer models and delays breast cancer development in a somatic breast cancer model. Our study suggests that uric acid accumulation plays an important role in activating TAK1, inducing DNA damage-induced MICA/B expression, and enhancing antitumor immunity.
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Subfamilia K de Receptores Similares a Lectina de Células NK , Ácido Úrico , Animales , ADN , Daño del ADN , Ligandos , Quinasas Quinasa Quinasa PAM , Ratones , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Ácido Úrico/farmacologíaRESUMEN
Flexible strain sensors have an irreplaceable role in critical and emerging fields, such as electronic skins, flexible robots, and prosthetics. Although numerous efforts have been made to improve sensor sensitivity to meet specific application scenarios, the signal-to-noise ratio (SNR) is an extremely critical and non-negligible indicator, which takes into account higher sensitivity, meaning that they can also detect the noise signals with high sensitivity. Coincidentally, scorpions with ultrasensitive vibration sensilla also face such a dilemma. Here, it is found that the scorpion ingeniously uses the viscoelastic material in front of its slit sensilla to realize efficient preprocessing of the signal. Its mechanism is that the loss factor of materials changes with frequency, affecting energy storage and transmission. Inspired by this ingenious strategy, a bioinspired strain sensor insensitive to a low strain rate was designed using a two-step template transfer method. As a result, its relative change in resistance reached 110% under the same strain (0.3197%) but with different strain rates (0.1 Hz and â¼20 Hz). The noncontact vibration experiments also show different responses to low-frequency vibration and high-frequency impact. Moreover, it can also be used as a typical flexible strain sensor. Under the tensile state, it has a gauge factor (GF) as high as 4596 upon 0.6% strain, and the response time is 140 ms. Therefore, it is expected that this strain sensor will be used in many important ultraprecision measurement fields, especially when the measured signal is small.
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Dispositivos Electrónicos Vestibles , VibraciónRESUMEN
Drug discovery focused on target proteins has been a successful strategy, but many diseases and biological processes lack obvious targets to enable such approaches. Here, to overcome this challenge, we describe a deep learning-based efficacy prediction system (DLEPS) that identifies drug candidates using a change in the gene expression profile in the diseased state as input. DLEPS was trained using chemically induced changes in transcriptional profiles from the L1000 project. We found that the changes in transcriptional profiles for previously unexamined molecules were predicted with a Pearson correlation coefficient of 0.74. We examined three disorders and experimentally tested the top drug candidates in mouse disease models. Validation showed that perillen, chikusetsusaponin IV and trametinib confer disease-relevant impacts against obesity, hyperuricemia and nonalcoholic steatohepatitis, respectively. DLEPS can generate insights into pathogenic mechanisms, and we demonstrate that the MEK-ERK signaling pathway is a target for developing agents against nonalcoholic steatohepatitis. Our findings suggest that DLEPS is an effective tool for drug repurposing and discovery.
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Aprendizaje Profundo , Animales , Descubrimiento de Drogas , Reposicionamiento de Medicamentos , Ratones , Proteínas/genética , Transcriptoma/genéticaRESUMEN
The sonic hedgehog (Shh) pathway is highly activated in a variety of malignancies and plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. Our recent study showed that the inhibitors of the Shh pathway such as cyclopamine (CP), a Smothened (SMO) inhibitor, and GANT61, a Gli1 inhibitor, have modest inhibitory effects on thyroid tumor cell proliferation and tumor growth. The objective of this study was to determine whether autophagy was induced by inhibition of the Shh pathway and could negatively regulate GANT61-induced apoptosis. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 induced autophagy in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines; whereas Gli1 overexpression suppressed autophagy. Mechanistic investigation revealed that inhibition of the Shh pathway activated TAK1 and its two downstream kinases, the c-Jun-terminal kinase (JNK) and AMP-activated protein kinase (AMPK). GANT61-induced autophagy was blocked by TAK1 siRNA and the inhibitors of TAK1 (5Z-7-oxozeaenol, 5Z), JNK (SP600125), and AMPK (Compound C, CC). Inhibition of autophagy by chloroquine and 5Z and by TAK1 and Beclin-1 siRNA enhanced GANT61-induced apoptosis and its antiproliferative activity. Our study has shown that inhibition of the Shh pathway induces autophagy by activating TAK1, whereas autophagy in turn suppresses GANT61-induced apoptosis. We have uncovered a previously unrecognized role of TAK1 in Shh pathway inhibition-induced autophagy and apoptosis.
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Proteínas Hedgehog/antagonistas & inhibidores , Glándula Tiroides/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Apoptosis , Autofagia , Proteínas Hedgehog/metabolismo , Humanos , Transducción de Señal , TransfecciónRESUMEN
A real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for the detection of Muscovy duck reovirus (MDRV) RNA in clinical samples is described. The assay is based on TaqMan-MGB technology, consisting of two primers and one probe labeled with the reporter dye 6-carboxyfluorescein that binds selectively to the sigma B-protein gene of MDRV. This technique also includes an Internal Positive Control (IPC). The real-time RT-PCR assay was able to detect MDRVs, whereas other common waterfowl-origin viral pathogens were not recognised by the established oligonucleotide set, thus showing that the test was specific for MDRV. The sensitivity of the assay was 2.83 × 101 copies/µL and was 100 times higher than that of the conventional RT-PCR. The variation coefficients of intra-assay and inter-assay were less than 1.5% which verified sufficient repeatability of this assay. The use of ß-actin mRNA as an IPC in order not to reduce the efficiency of the assay was adopted. The detection for 100 clinical samples showed that the positive rate of the established TaqMan-MGB real-time RT-PCR method was 87% (87/100), while the positive rate of the conventional RT-PCR was 83% (83/100), with the coincidence rate was 97.14%. Sensitivity and positive rate for clinical samples of TaqMan fluorescent quantitative RT-PCR were higher than conventional RT-PCR. The high specificity, sensitivity, and rapidity TaqMan-MGB real-time RT-PCR assay with the use of IPC to monitor for false negative results can make this method suitable for the pathogenic surveillance and epidemiological investigation of MDRV infection.
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Patos/virología , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Reoviridae/genética , Reoviridae/aislamiento & purificación , Animales , Estándares de Referencia , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sensibilidad y EspecificidadRESUMEN
Time-resolved fluorescence lifetime imaging (FLIM) in the near-infrared region of 900-1700 nm not only allows a deep tissue penetration depth but also offers the unique benefit of the quantitative visualization of molecular events in vivo and is independent of local luminescence intensity and fluorophore concentration. Herein, we report the design of a wide-range pH sensitive molecular probe based on Yb3+ porphyrinate. The Yb3+ probe shows increasing NIR emission and lifetime with pK a values of ca. 6.6 from pH 9.0 and 5.0 and also displays an elongated lifetime from ca. 135 to 170 µs at lower pH values (5.0-1.0) due to aggregation and reduced exposure to water at low pH values. Importantly, the probe is able to monitor a wide range of in vivo gastrointestinal pH values in mice models and the potential applications in imaging-guided gastrointestinal diagnostics and therapeutics were revealed. This study shows that lifetime contrast is important for preclinical imaging; lanthanide complexes could be successfully used in the design of stimuli-responsive NIR τ probes for advanced in vivo imaging.
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OBJECTIVES: To describe the clinical characteristics and management of patients hospitalised with community-acquired pneumonia (CAP) in China. DESIGN: This was a multicentre, retrospective, observational study. SETTING: 13 teaching hospitals in northern, central and southern China from 1 January 2014 to 31 December 2014 PARTICIPANTS: Information on hospitalised patients aged ≥14 years with radiographically confirmed pneumonia with illness onset in the community was collected using standard case report forms. PRIMARY AND SECONDARY OUTCOME MEASURES: Resource use for CAP management. RESULTS: Of 14 793 patients screened, 5828 with radiographically confirmed CAP were included in the final analysis. Low mortality risk patients with a CURB-65 score 0-1 and Pneumonia Severity Index risk class I-II accounted for 81.2% (4434/5594) and 56.4% (2034/3609) patients, respectively. 21.7% (1111/5130) patients had already achieved clinical stability on admission. A definite or probable pathogen was identified only in 12.7% (738/5828) patients. 40.9% (1575/3852) patients without pseudomonal infection risk factors received antimicrobial overtreatment regimens. The median duration between clinical stability to discharge was 5.0 days with 30-day mortality of 4.2%. CONCLUSIONS: These data demonstrated the overuse of health resources in CAP management, indicating that there is potential for improvement and substantial savings to healthcare systems in China. TRIAL REGISTRATION NUMBER: NCT02489578; Results.