The development of effective antifungal agents remains a big challenge in view of the close evolutionary relationship between mammalian cells and fungi. Moreover, rapid mutations of fungal receptors ...at the molecular level result in the emergence of drug resistance. Here, with low tendency to develop drug-resistance, the subcellular organelle mitochondrion is exploited as an alternative target for efficient fungal killing by photodynamic therapy (PDT) of mitochondrial-targeting luminogens with aggregation-induced emission characteristics (AIEgens). With cationic isoquinolinium (IQ) moiety and proper hydrophobicity, three AIEgens, namely, IQ-TPE-2O, IQ-Cm, and IQ-TPA, can preferentially accumulate at the mitochondria of fungi over the mammalian cells. Upon white light irradiation, these AIEgens efficiently generate reactive 1O2, which causes irreversible damage to fungal mitochondria and further triggers the fungal death. Among them, IQ-TPA shows the highest PDT efficiency against fungi and negligible toxicity to mammalian cells, achieving the selective and highly efficient killing of fungi. Furthermore, we tested the clinical utility of this PDT strategy by treating fungal keratitis on a fungus-infected rabbit model. It was demonstrated that IQ-TPA presents obviously better therapeutic effects as compared with the clinically used rose bengal, suggesting the success of this PDT strategy and its great potential for clinical treatment of fungal infections.
Background: To clarify the role of intention to treat for patients with localized nasal natural killer (NK)/T-cell lymphoma, and to determine the prognostic factors for these patients. Patients and ...methods: We conducted a retrospective review of 46 patients with localized nasal NK/T-cell lymphomas treated at a single institute between January 1988 and July 2002. Results: The type of intended treatment was a significant factor for overall survival (OS) (5-year OS: RT versus CT = 83.3% versus 28.6%, P = 0.0269) or failure-free survival (FFS) (5-year FFS: RT versus CT = 83.3% versus 27.1%, P = 0.0247). In the intended chemotherapy group, salvage with radiotherapy was superior to chemotherapy alone for OS (5-year OS: 42.2% versus 20.0%, P = 0.0252) or FFS (5-year FFS: 41.0% versus 20.0%, P = 0.0352). On multivariate analysis, both N stage and serum lactate hehydrogenase level were independent factors for OS and FFS. No radiotherapy was an independent adverse factor for OS; advanced T stage and more than one extranodal involvement were independent adverse factors for FFS. Conclusions: Patients with localized nasal NK/T-cell lymphomas were better managed with radiotherapy as front-line therapy. The advantage of radiotherapy persisted even as palliative therapy after chemotherapy.
This paper studies experimentally the coalescence mechanism between two parallel three-dimensional (3-D) pre-existing surface cracks in granite specimen under uniaxial compression. The bridge angles ...between the two pre-existing cracks vary from 0° to 135°. The digital speckle correlation method (DSCM) is used to analyze the captured images producing strain fields during the cracking process, and thus reveals the mode of cracking (either tensile, shear or their combination). Petal crack that initiates from internal crack fronts of the pre-existing surface cracks plays an important role in crack initiation, propagation and coalescence. Microcracks underneath the specimen surface appear as white patches on the surface, which always appear preceding the appearance of surface macrocracks (either wing or anti-wing cracks). Cracks, which grow in a direction opposite to that of wing cracks, were consistently observed before the appearance of wing cracks; and these cracks are therefore called “anti-wing cracks”. In addition, DSCM results suggest that wing crack and anti-wing crack are tensile during initiation but may subsequently turn into mixed mode. The coalescence between the two 3-D pre-existing surface cracks takes place both on the specimen surface (through wing, anti-wing cracks or secondary cracks) and inside the specimen (through internal petal cracks). Depending on the bridge angle β between the two pre-existing cracks, there can be no crack coalescence, coalescence in forms of tensile cracks (tensile mode), coalescence by mixed mode cracks (mixed mode), and finally coalescence in forms of a secondary crack jointing an initiated wing or anti-wing crack, emanating from one tip, to the other tip (secondary crack mode).
•Cracking mode on specimen surface is identified by the digital speckle correlation method.•Petal crack plays an important role in surface crack development.•Coalescence between surface cracks occurs both on surface and inside of specimen.•Four surface crack coalescence patterns are classified.
It is undoubted the important role of cells in biology and medicine, but worldwide misidentified and cross-contaminated cell lines have caused much trouble in related fields. Herein, three kinds of ...supramolecular AIE (aggregation-induced emission) nanoassemblies were constructed by the host–guest interaction between tetraphenylethene (TPE) derivatives and cucurbit8uril (CB8). Based on the recognized mechanism of AIE, the TPE derivatives could achieve stronger fluorescence emission and higher fluorescence quantum yield after assembling with CB8. Moreover, the constructed supramolecular AIE complexes obtained well-confirmed nanostructures and exhibited different sizes and shapes. Correspondingly, they generated characteristic biological properties and fluorescence enhancement of cells. Inspired by the concept of Big Data Analysis, these fluorescence signals were further transformed into a unique fingerprint of cells via linear discriminant analysis. Immediately, we realized the veracious identification between a normal cell line, two cancer cell lines, and two metastasized cancer cell lines in a qualitative analysis. More importantly, it was well used to monitor the evaluation of cross-contaminated cells and the discrimination of cancer cells. As a proper bioapplication of ideal supramolecular nanomaterials, this system was easy to learn and apply, and the whole procedure was kept to 20 min, without cell disruption, centrifugation, or washing steps.
Cancer cell discrimination and cellular viability monitoring are closely related to human health. A universal and convenient fluorescence system with a dual function of wide-spectrum cancer cell ...discrimination and dynamic cellular viability monitoring is desperately needed, and is still extremely challenging. Herein we present a series of aggregation-induced emission luminogens (AIEgens) (denoted as IVP) which can allow accurate discrimination between cancer and normal cells and dynamic monitoring of cellular viability through mitochondria-nucleolus migration. By regulating the lengths and positions of alkyl chains in IVP molecules, we systematically studied the discrimination behavior of these AIEgens between cancer cells and normal cells and further investigated how they can migrate between the mitochondria and nucleolus based on the change of mitochondrial membrane potential (Δ
Ψ
m
). Using
IVP-02
as a model molecule, wash-free bioimaging, excellent two-photon properties, and low cytotoxicity were demonstrated. This present work proves that these designed IVP AIEgens show great potential for cancer identification and metastasis monitoring, as well as activity evaluation and screening of drugs.
We present a series of AIEgens for cancer cell discrimination and dynamic viability monitoring.
•fMRI and multi-modal simple response task elucidate processing speed.•First-order vector autoregression outperformed other analysis methods.•Effective connectivities within cerebello-frontal network ...subserve cognitive speed.•Long- and short-range paths suggest control and rule-based response processes.
Processing speed is an important construct in understanding cognition. This study was aimed to control task specificity for understanding the neural mechanisms underlying cognitive processing speed. Forty young adult subjects performed attention tasks of two modalities (auditory and visual) and two levels of task rules (compatible and incompatible). Block-design fMRI captured BOLD signals during the tasks. Thirteen regions of interest were defined with reference to publicly available activation maps for processing speed tasks. Cognitive speed was derived from task reaction times, which yielded six sets of connectivity measures. Mixed-effect LASSO regression revealed six significant paths suggestive of a cerebello-frontal network predicting the cognitive speed. Among them, three are long range (two fronto-cerebellar, one cerebello-frontal), and three are short range (fronto-frontal, cerebello-cerebellar, and cerebello-thalamic). The long-range connections are likely to relate to cognitive control, and the short-range connections relate to rule-based stimulus-response processes. The revealed neural network suggests that automaticity, acting on the task rules and interplaying with effortful top–down attentional control, accounts for cognitive speed.
Visually identifying pathogens favors rapid diagnosis at the point-of-care testing level. Here, we developed a microenvironment-sensitive aggregation-induced emission luminogen (AIEgen), namely ...IQ-Cm, for achieving fast discrimination of Gram-negative bacteria, Gram-positive bacteria and fungi by the naked-eye. With a twisted donor-acceptor and multi-rotor structure, IQ-Cm shows twisted intramolecular charge transfer (TICT) and AIE properties with sensitive fluorescence color response to the microenvironment of pathogens. Driven by the intrinsic structural differences of pathogens, IQ-Cm with a cationic isoquinolinium moiety and a membrane-active coumarin unit as the targeting and interacting groups selectively locates in different sites of three pathogens and gives three naked-eye discernible emission colors. Gram-negative bacteria are weak pink, Gram-positive bacteria are orange-red and fungi are bright yellow. Therefore, based on their distinctive fluorescence response, IQ-Cm can directly discriminate the three pathogens at the cell level under a fluorescence microscope. Furthermore, we demonstrated the feasibility of IQ-Cm as a visual probe for fast diagnosis of urinary tract infections, timely monitoring of hospital-acquired infection processes and fast detection of molds in the food field. This simple visualization strategy based on one single AIEgen provides a promising platform for rapid pathogen detection and point-of-care diagnosis.
A simple AIEgen with three emission colors achieves rapid identification of Gram-negative bacteria, Gram-positive bacteria and fungi.
Cisplatin and paclitaxel are standard chemotherapy for metastatic ovarian cancer, but with limited efficacy. Cancer stem/progenitor cells (or tumor-initiating cells, TICs) are hypothesized to be ...chemoresistant, and the existence of TICs in ovarian cancer has been previously demonstrated. However, the key signals and molecular events regulating the formation and expansion of ovarian tumor-initiating cells (OTICs) remain elusive. Here, we show that c-Kit is not just a marker of OTICs, but also a critical mediator of the phenotype that can be a viable target for the treatment of ovarian cancer. In contrast to non-OICs, c-Kit was overexpressed in OTICs. Moreover, the use of small interfering RNA to inhibit c-Kit expression markedly attenuated the number and size of OTIC subpopulations, inhibited the expression of stem cell markers and decreased the tumorigenic capabilities of OTICs. Imatinib (Gleevec), a clinical drug that blocks c-Kit kinase activity, also demonstrated its inhibition potency on OTICs. In addition, cisplatin/paclitaxel, which killed non-OTICs, with c-Kit knockdown or imatinib revealed that this was critically required for intervening ovarian cancer progression and recurrence in vitro and in xenograft tumors in vivo. Similar results were obtained with OTICs derived from ovarian carcinoma patients. Studies into the mechanisms suggest an important role for the activation of Wnt/β-catenin and ATP-binding cassette G2 downstream of c-Kit. The tumor-promoting microenvironment, such as hypoxia, could promote OTICs via upregulation of c-Kit expression. These results unravel an integral role for c-Kit in ovarian neoplastic processes and shed light on its mechanisms of action.
The uniqueness of neural processes between allocentric and egocentric spatial coding has been controversial. The distinctive paradigms used in previous studies for manipulating spatial coding could ...have attributed for the inconsistent results. This study was aimed to generate converging evidence from previous functional brain imaging experiments for collating neural substrates associated with these two types of spatial coding. An additional aim was to test whether test‐taking processes would have influenced the results. We obtained coordinate‐based functional neuroimaging data for 447 subjects and performed activation likelihood estimation (ALE) meta‐analysis. Among the 28 experiments, the results indicate two common clusters of convergence. They were the right precuneus and the right superior frontal gyrus as parts of the parieto‐frontal circuit. Between‐type differences were in the parieto‐occipital circuit, with allocentric showing convergence in the superior occipital gyrus (SOG) cluster compared with egocentric showing convergence in the middle occipital gyrus (MOG) cluster. Task‐specific influences were only found in allocentric spatial coding. Spatial judgment‐oriented tasks seem to increase the demands on manipulating spatial relationships among the visual objects, while spatial navigation tasks seem to increase the demands on maintaining object representations. Our findings address the theoretical controversies on spatial coding that both the allocentric and egocentric types are common in their processes mediated by the parieto‐frontal network, while unique and additional processes in the allocentric type are mediated by the parieto‐occipital network. The positive results on possible task‐specific confound offer insights into the future design of spatial tasks for eliciting spatial coding processes.
An Activation Likelihood Estimation (ALE) analysis was carried out to converge neural substrates subserving aSC and eSC. Both allocentric and egocentric spatial coding share common convergence in the parieto‐frontal circuit. Differences in the convergence between the two types of spatial coding are in the parieto‐occipital circuit. Only allocentric but not egocentric spatial coding may have influenced by task‐specific processes.
Iatrogenic ureteral injury is a dreaded complication of abdominal and pelvic surgeries, and thus, intraoperative identification of ureters is of paramount importance but lacks efficient methods and ...probes. Herein, we used near-infrared II (NIR-II, 1000–1700 nm) fluorescence imaging with advantages of higher spatial resolution, deeper tissue penetration, lower light scattering, and less tissue autofluorescence to identify ureters by aggregation-induced emission luminogen dots (AIE dots). The intraoperative ureteral injuries and common ureteral diseases can be visualized timely and precisely. Due to the longer emission wavelength and higher quantum yield of the AIE dots, it largely outperforms the commercial indocyanine green dye in brightness and penetration depth. It was the first time to realize the intraoperative identification of ureters in vivo using NIR-II imaging. Thus, our work provides a new platform for intraoperative monitoring during clinical operation.
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