The vacuolar fusion regulated by HOPS complex promotes hyphal initiation and penetration in Candida albicans.

The transition between yeast and hyphae is crucial for regulating the commensalism and pathogenicity in Candida albicans. The mechanisms that affect the invasion of hyphae in solid media, whose deficiency is more related to the pathogenicity of C. albicans, have not been elucidated. Here, we found that the disruption of VAM6 or VPS41 which are components of the homotypic vacuolar fusion and protein sorting (HOPS) complex, or the Rab GTPase YPT72, all responsible for vacuole fusion, led to defects in hyphal growth in both liquid and solid media, but more pronounced on solid agar. The phenotypes of vac8Δ/Δ and GTR1OE-vam6Δ/Δ mutants indicated that these deficiencies are mainly caused by the reduced mechanical forces that drive agar and organs penetration, and confirmed that large vacuoles are required for hyphal mechanical penetration. In summary, our study revealed that large vacuoles generated by vacuolar fusion support hyphal penetration and provided a perspective to refocus attention on the role of solid agar in evaluating C. albicans invasion.

BODIPY-Based NIR Trackers with Acidity-Driven Amphiphilicity for STED Super-Resolution Imaging of Lysosomal Membranes.

Although super-resolution imaging provides a great opportunity to disclose the structures of living cells at the nanoscale level, resolving the structural details of organelles is highly dependent on the targeting accuracy and photophysical properties of fluorescence trackers. Herein, we report a series of ultrabright and photostable trackers of lysosomal membranes for super-resolution imaging using stimulated emission depletion microscopy (STED). These trackers are composed of lipophilic NIR BODIPY derivatives and ionizable tertiary amines. This structural feature enables accurate targeting of the lysosomal membrane through the formation of transient amphiphilicity driven by the acidity in the lysosome. As a representative, Lyso-700 is applied for STED-based super-resolution imaging of the lysosomal membrane of living macrophages. By use of Lyso-700, the interaction details between lysosomes of macrophages and fungi are visualized. Overall, these trackers display great potential as advanced lysosome trackers and merit further evaluation for lysosome-related studies.

Influencing factors of the treatment level of elderly care workers and their career development prospects.

BACKGROUND: The increasingly aging population in current China has encouraged the emergence of the diversified and multi-level elderly care service industry, and the demand for high-quality elderly life with the help of elderly caregivers continues to grow. METHODS: Based on the existing questionnaire data, this article explores the influencing factors of the treatment level of care staff, and explores their future development prospects. RESULTS: The results show that whether they have participated in relevant vocational skills competitions, whether they have worked overtime, whether they have overtime wages, and their monthly income have significant effects on their satisfaction of treatment levels. Elderly care workers who have participated in skills competitions are more satisfied about their salary. In addition, workers who rarely and occasionally work overtime are more satisfied compared with those who have never worked overtime; Caregivers with a monthly income of 5,000-6,999 yuan are more satisfied with their salary and treatment than those with below 3,000 yuan. CONCLUSION: Therefore, in order to better match the supply and demand of care workers, we should provide formal training and skill competitions for them, appropriately increase their salary level and reasonably arrange their working hours, so as to attract more professional talents into elderly care industry.

Enhanced Fluorescence by Inter/Intramolecular Hydrogen Bonding in Si-Substituted Coumarins.

Introducing heteroatoms in organic fluorophores offers a unique strategy to tune their photophysical properties without dangling structural decorations. Silicon-substituted coumarins (Si-coumarins) are the analogues of coumarin with the substitution of ester oxygen atoms by silicon atoms. In Si-coumarins, significant fluorescence enhancement in protic solvents through the formation of inter/intramolecular hydrogen bonds (H-bonds) offered great potential in various aspects with many unique photophysical properties. The energies of nπ* and ππ* states in Si-coumarins are elaborately tuned by inter/intramolecular H-bonds and solvents after incorporating silicon atoms. For example, the inter/intramolecular H-bonds elevate the energy of the nπ* state in protic solvents, leading to an enlarged energy gap between the nπ* and ππ* states. Thus, fluorescence is enhanced by reducing the nonradiative transition through the nπ* state in coumarins, resulting in many unique photophysical properties. The understanding of H-bonds in Si-coumarins offers more potential strategies for the design of novel fluorophores.

A Substituted-Rhodamine-Based Reversible Fluorescent Probe for In Vivo Quantification of Glutathione.

Quantifying glutathione (GSH) in cells and organisms is of great significance for understanding the mechanism of oxidative stress in various physiological and pathological processes. However, the quantification by fluorescence bioimaging in living tissues has much stricter requirements than the "Petri dish"-cultured cells in flat plates. Based on the evaluation of the electronic structure and steric hindrance-tuned reactivity of phospha-substituted rhodamine with GSH, a reversible Förster resonance energy transfer (FRET) probe ZpSiP with a distinct performance (Kd =4.9 mM, t1/2 =0.57 s, k=81 M-1 s-1 ) is developed for real time quantifying GSH in living cells. Furthermore, the near-infrared (NIR) probe succeeded in sensitively tracking the dynamics of GSH in the real organisms bearing tumors, chronic renal failure, and liver fibrosis for unveiling the related pathological processes. We believe that the advance in chemistry with quantitative analysis methods will initiate more promising progress and broad applications.

Fast Prediction of Lipophilicity of Organofluorine Molecules: Deep Learning-Derived Polarity Characters and Experimental Tests.

Fast and accurate estimation of lipophilicity for organofluorine molecules is in great demand for accelerating drug and materials discovery. A lipophilicity data set of organofluorine molecules (OFL data set), containing 1907 samples, is constructed through density functional theory (DFT) calculations and experimental measurements. An efficient and interpretable model, called PoLogP, is developed to predict the n-octanol/water partition coefficient, log Po/w, of organofluorine molecules on the basis of the descriptors of polarization, which is a combination of polarity descriptors, including the molecular polarity index and molecular polarizability (α), and hydrogen bond (HBs) index, consisting of the number of donors (NHBD) and acceptors (NHBA and NHB-FA). The present PoLogP with a combination of polarity descriptors is demonstrated to perform better than the dipole moment (µ) alone for the F-contained molecules. With the aid of a multilevel attention graph convolutional neural network model, the fast generation of polarity descriptors of organofluorine molecules could be achieved with the DFT accuracy based only on a topological molecular graph structure. The performance of PoLogP is further validated on synthesized organofluorine molecules and 2626 non-fluorinated molecules with satisfactory accuracy, highlighting the potential usage of PoLogP in high-throughput screening of the functional molecules with the desired solubility in various solvent media.

Molecular partition coefficient from machine learning with polarization and entropy embedded atom-centered symmetry functions.

Efficient prediction of the partition coefficient (log P) between polar and non-polar phases could shorten the cycle of drug and materials design. In this work, a descriptor, named 〈q - ACSFs〉conf, is proposed to take the explicit polarization effects in the polar phase and the conformation ensemble of energetic and entropic significance in the non-polar phase into consideration. The polarization effects are involved by embedding the partial charge directly derived from force fields or quantum chemistry calculations into the atom-centered symmetry functions (ACSFs), together with the entropy effects, which are averaged according to the Boltzmann distribution of different conformations taken from the similarity matrix. The model was trained with high-dimensional neural networks (HDNNs) on a public dataset PhysProp (with 41 039 samples). Satisfactory log P prediction performance was achieved on three other datasets, namely, Martel (707 molecules), Star & Non-Star (266) and Huuskonen (1870). The present 〈q - ACSFs〉conf model was also applicable to n-carboxylic acids with the number of carbons ranging from 2 to 14 and 54 kinds of organic solvent. It is easy to apply the present method to arbitrary sized systems and give a transferable atom-based partition coefficient.

Hydrogen Bond-Enhanced Nanoaggregation and Antisolvatochromic Fluorescence for Protein-Recognition by Si-Coumarins.

Silicon-substituted coumarin (SiC) was established as a substantial family of both intramolecular and intermolecular hydrogen bond (H-bond) enhanced fluorescent probes for sensitively tracking proteins in vivo through the assemble and disassemble of its nanoaggregates. The intramolecular H-bond in SiC has led to significant aggregation, antisolvatochromism, and strong fluorescence with bathochromically shifted spectra into far-red or near-infrared (NIR) regions in polar, protic environments. Without further furnishing with organic linkers, the compact skeleton of SiC bearing H-bond has ensured sensitively and selectively sensing the targeting proteins with the protic reaction pockets through efficient disassemble of the aggregates. In the existence of strong intermolecular H-bonds with the target protein pocket, SiC resolved as high as >250-fold fluorescence enhancement. Selectively tracking proteins, including human serum albumin, human carbonic anhydrase (hCAII), avidin, SNAP-tag protein, and translocator protein, has confirmed SiC a versatile skeleton for sensitively monitoring proteins in complicated biological systems.

STED Imaging the Dynamics of Lysosomes by Dually Fluorogenic Si-Rhodamine.

Super-resolution microscopy (SRM) imaging of the finite subcellular structures and subtle bioactivities inside organelles delivers abundant cellular information with high fidelity to unravel the intricate biological processes. An ideal fluorescent probe with precise control of fluorescence is critical in SRM technique like stimulated emission depletion (STED). Si-rhodamine was decorated with both targeting group and H+ -receptor, affording the dually fluorogenic Si-rhodamine in which the NIR fluorescence was efficiently controlled by the coalescent of spirolactone-zwitterion equilibrium and PeT mechanism. The dually fluorogenic characters of the probe offer a perfect mutual enhancement in sensitivity, specificity and spatial resolution. Strong fluorescence only released in the existence of targeting protein at acidic lysosomal pH, ensured precisely tracking the dynamic of lysosomal structure and pH in living cells by STED.

Shear viscosity prediction of alcohols, hydrocarbons, halogenated, carbonyl, nitrogen-containing, and sulfur compounds using the variable force fields.

Viscosity of organic liquids is an important physical property in applications of printing, pharmaceuticals, oil extracting, engineering, and chemical processes. Experimental measurement is a direct but time-consuming process. Accurately predicting the viscosity with a broad range of chemical diversity is still a great challenge. In this work, a protocol named Variable Force Field (VaFF) was implemented to efficiently vary the force field parameters, especially λvdW, for the van der Waals term for the shear viscosity prediction of 75 organic liquid molecules with viscosity ranging from -9 to 0 in their nature logarithm and containing diverse chemical functional groups, such as alcoholic hydroxyl, carbonyl, and halogenated groups. Feature learning was applied for the viscosity prediction, and the selected features indicated that the hydrogen bonding interactions and the number of atoms and rings play important roles in the property of viscosity. The shear viscosity prediction of alcohols is very difficult owing to the existence of relative strong intermolecular hydrogen bonding interaction as reflected by density functional theory binding energies. From radial and spatial distribution functions of methanol, we found that the van der Waals related parameters λvdW are more crucial to the viscosity prediction than the rotation related parameters, λtor. With the variable λvdW-based all-atom optimized potentials for liquid simulations force field, a great improvement was observed in the viscosity prediction for alcohols. The simplicity and uniformity of VaFF make it an efficient tool for the prediction of viscosity and other related properties in the rational design of materials with the specific properties.

Far-red imaging of ß-galactosidase through a phospha-fluorescein.

The introduction of phosphine oxide into a fluorescein scaffold has yielded phospha-fluorescein with bathochromically shifted spectra, reliable photostability and solubility. Moreover, ratiometric and turn-on fluorescence in the decaging process has ensured that the phospha-fluorescein is a unique scaffold for fluorescence bioimaging. Probe DiMe-PF-Gal without further structural decoration was designed for accurately monitoring ß-galactosidase in vivo.

Combination of autoimmune pancreatitis and peripheral neuropathy on an IgG4-related disease patient with 4 years following-up.

Type1 autoimmune pancreatitis (AIP) is the first recognized and the most common manifestation of IgG4-related disease. However, AIP patient presented with neuropathy in the extremities have not been reported previously. We reported a rare combination of autoimmune pancreatitis and peripheral neuropathy on an IgG4-related disease patient based on histological features to expand the clinical spectrum of IgG4-related disease.

Acridinium Benzoates for Ratiometric Fluorescence Imaging.

Acridinium benzoate was developed as a unique ICT-based fluorescent scaffold for both ratiometric and turn-on fluorescence imaging through decaging of the phenolic hydroxyl groups. Two fluorescent probes, Acr1-H2 O2 and Acr1-ß-gal, were developed for the fluorescence imaging of H2 O2 and ß-galactosidase in vivo.

Asymmetric Si-rhodamine scaffolds: rational design of pH-durable protease-activated NIR probes in vivo.

A group of asymmetric Si-rhodamine scaffolds was designed for protease-activated NIR probes. Dual pH-inertia for both spirocyclized fluorescent probes and fluorescent products of zwitterions form over a wide range of pH (4.0-11.0). Leucine aminopeptidase (LAP) and γ-glutamyl transpeptidase (GGT) were monitored by fluorescent imaging in vivo.