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Filamentous cell growth is a vital property of fungal pathogens. The mechanisms of filamentation in the emerging multidrug-resistant fungal pathogen Candida auris are poorly understood. Here, we show that exposure of C. auris to glycerol triggers a rod-like filamentation-competent (RL-FC) phenotype, which forms elongated filamentous cells after a prolonged culture period. Whole-genome sequencing analysis reveals that all RL-FC isolates harbor a mutation in the C2H2 zinc finger transcription factor-encoding gene GFC1 (Gfc1 variants). Deletion of GFC1 leads to an RL-FC phenotype similar to that observed in Gfc1 variants. We further demonstrate that GFC1 mutation causes enhanced fatty acid β-oxidation metabolism and thereby promotes RL-FC/filamentous growth. This regulation is achieved through a Multiple Carbon source Utilizer (Mcu1)-dependent mechanism. Interestingly, both the evolved RL-FC isolates and the gfc1Δ mutant exhibit an enhanced ability to colonize the skin. Our results reveal that glycerol-mediated GFC1 mutations are beneficial during C. auris skin colonization and infection.

BackgroundWhole Slide Image (WSI) analysis, driven by deep learning algorithms, has the potential to revolutionize tumor detection, classification, and treatment response prediction. However, challenges persist, such as limited model generalizability across various cancer types, the labor-intensive nature of patch-level annotation, and the necessity of integrating multi-magnification information to attain a comprehensive understanding of pathological patterns.MethodsIn response to these challenges, we introduce MAMILNet, an innovative multi-scale attentional multi-instance learning framework for WSI analysis. The incorporation of attention mechanisms into MAMILNet contributes to its exceptional generalizability across diverse cancer types and prediction tasks. This model considers whole slides as “bags” and individual patches as “instances.” By adopting this approach, MAMILNet effectively eliminates the requirement for intricate patch-level labeling, significantly reducing the manual workload for pathologists. To enhance prediction accuracy, the model employs a multi-scale “consultation” strategy, facilitating the aggregation of test outcomes from various magnifications.ResultsOur assessment of MAMILNet encompasses 1171 cases encompassing a wide range of cancer types, showcasing its effectiveness in predicting complex tasks. Remarkably, MAMILNet achieved impressive results in distinct domains: for breast cancer tumor detection, the Area Under the Curve (AUC) was 0.8872, with an Accuracy of 0.8760. In the realm of lung cancer typing diagnosis, it achieved an AUC of 0.9551 and an Accuracy of 0.9095. Furthermore, in predicting drug therapy responses for ovarian cancer, MAMILNet achieved an AUC of 0.7358 and an Accuracy of 0.7341.ConclusionThe outcomes of this study underscore the potential of MAMILNet in driving the advancement of precision medicine and individualized treatment planning within the field of oncology. By effectively addressing challenges related to model generalization, annotation workload, and multi-magnification integration, MAMILNet shows promise in enhancing healthcare outcomes for cancer patients. The framework’s success in accurately detecting breast tumors, diagnosing lung cancer types, and predicting ovarian cancer therapy responses highlights its significant contribution to the field and paves the way for improved patient care.

ABSTRACTCandida albicans is a normal resident of the human oral cavity. It is also the most common fungal pathogen, causing various oral diseases, particularly in immunocompromised individuals. Chlorhexidine digluconate (CHG) is a broad-spectrum antimicrobial agent widely used in dental practice and has been recommended to treat oral candidiasis. However, its action mechanism against the fungal pathogen C. albicans remains poorly understood. The aim of the present study was to investigate the effect of CHG at sub-lethal concentrations against C. albicans. CHG inhibited the growth of C. albicans in a dose- and time-dependent manner. Cells treated with CHG exhibited altered membrane permeability, reduced metabolic activity, and enhanced metal ion and reactive oxygen species (ROS) accumulation. Copper-sensing transcription factor Mac1, iron-sensing transcription factors Sfu1 and Sef2, and copper transporter Ctr1 regulated intracellular metal ion and ROS homeostasis in response to CHG. Deletion of MAC1, SFU1, or SEF2 increased intracellular ROS production and cell susceptibility to CHG. This study revealed a novel mechanism by which CHG induced apoptosis of C. albicans cells through the disruption of metal ion and ROS homeostasis, which may help to identify new targets for fungal infections.

We investigated the electron transport properties of n-GaN under an Ohmic-metal. Hall measurement results were compared for n-GaN (A) before Ti-based metal deposition, (B) after Ti-based metal deposition but before annealing, (C) after Ohmic annealing, and (D) after Ohmic-metal removal, where multi-probe-Hall device measurements are required for (C), while the others, (A), (B), and (D), can be characterized by conventional Hall device measurements. The multi-probe-Hall device measurements for (C) elucidated that, under the Ohmic-metal, the electron concentration is increased and the electron mobility is enhanced in comparison with those for the other cases, (A), (B), and (D). The increased electron concentration indicates that high-density doping takes place in the n-GaN by the Ohmic annealing. However, the high-density doping is not observed after the Ohmic-metal removal. Moreover, the electron mobility enhancement under the Ohmic-metal cannot be explained by donor doping with ionized impurity scattering. These suggest that, under the Ohmic-metal, high-density donors are not formed, and high-density polarization doping owing to strain from the Ohmic-metal takes place. From theoretical calculations, we clarified that the increase in the electron density by polarization doping without donors leads to the suppression of ionized impurity scattering and consequently the electron mobility enhancement.

PurposeThe aim of this study was to evaluate the value of different multiparametric MRI-based radiomics models in differentiating stage IA endometrial cancer (EC) from benign endometrial lesions.MethodsThe data of patients with endometrial lesions from two centers were collected. The radiomics features were extracted from T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) map, and late contrast-enhanced T1-weighted imaging (LCE-T1WI). After data dimension reduction and feature selection, nine machine learning algorithms were conducted to determine which was the optimal radiomics model for differential diagnosis. The univariate analyses and logistic regression (LR) were performed to reduce valueless clinical parameters and to develop the clinical model. A nomogram using the radscores combined with clinical parameters was developed. Two integrated models were obtained respectively by the ensemble strategy and stacking algorithm based on the clinical model and optimal radiomics model. The area under the curve (AUC), clinical decisive curve (CDC), net reclassification index (NRI), and integrated discrimination index (IDI) were used to evaluate the performance and clinical benefits of the models.ResultsA total of 371 patients were incorporated. The LR model was the optimal radiomics model with the highest average AUC (0.854) and accuracy (0.802) in the internal and external validation groups (AUC = 0.910 and 0.798, respectively), and outperformed the clinical model (AUC = 0.739 and 0.592, respectively) or the radiologist (AUC = 0.768 and 0.628, respectively). The nomogram (AUC = 0.917 and 0.802, respectively) achieved better discrimination performance than the optimal radiomics model in two validation groups. The stacking model (AUC = 0.915) and ensemble model (AUC = 0.918) had a similar performance compared with the nomogram in the internal validation group, whereas the AUCs of the stacking model (AUC = 0.792) and ensemble model (AUC = 0.794) were lower than those of the nomogram and radiomics model in the external validation group. According to the CDC, NRI, and IDI, the optimal radiomics model, nomogram, stacking model, and ensemble model achieved good net benefits.ConclusionsMultiparametric MRI-based radiomics models can non-invasively differentiate stage IA EC from benign endometrial lesions, and LR is the best machine learning algorithm. The nomogram presents excellent and stable diagnostic efficiency.

Direct dehydrogenation has been a thematic research area resulting from the energy shortage and petroleum gas upgrading scenario. Here, the authors fabricate fully exposed Pt3 clusters and correlate dehydrogenation activity with average coordination number of Pt-Pt bond.

Enhancing the intrinsic activity and space time yield of Cu based heterogeneous methanol synthesis catalysts is one of the major topics in CO2 hydrogenation. Here the authors develop a highly active inverse catalyst composed of fine ZrO2 islands dispersed on metallic Cu nanoparticles.

Direct detector device (DDD) cameras have revolutionized electron cryomicroscopy (cryoEM) with their high detective quantum efficiency (DQE) and output of movie data. A high ratio of camera frame rate (frames per second) to camera exposure rate (electrons per pixel per second) allows electron counting, which further improves the DQE and enables the recording of super-resolution information. Movie output also allows the correction of specimen movement and compensation for radiation damage. However, these movies come at the cost of producing large volumes of data. It is common practice to sum groups of successive camera frames to reduce the final frame rate, and therefore the file size, to one suitable for storage and image processing. This reduction in the temporal resolution of the camera requires decisions to be made during data acquisition that may result in the loss of information that could have been advantageous during image analysis. Here, experimental analysis of a new electron-event representation (EER) data format for electron-counting DDD movies is presented, which is enabled by new hardware developed by Thermo Fisher Scientific for their Falcon DDD cameras. This format enables the recording of DDD movies at the raw camera frame rate without sacrificing either spatial or temporal resolution. Experimental data demonstrate that the method retains super-resolution information and allows the correction of specimen movement at the physical frame rate of the camera while maintaining manageable file sizes. The EER format will enable the development of new methods that can utilize the full spatial and temporal resolution of DDD cameras.

ABSTRACT Phenotypic plasticity is a common strategy adopted by fungal pathogens to adapt to diverse host environments. Candida haemulonii is an emerging multidrug-resistant human pathogen that is closely related to Candida auris. Until recently, it was assumed that C. haemulonii is incapable of phenotypic switching or filamentous growth. In this study, we report the identification of three distinct phenotypes in C. haemulonii: white, pink, and filament. The white and pink phenotypes differ in cellular size, colony morphology, and coloration on phloxine B- or CuSO4-containing agar. Switching between the white and pink cell types is heritable and reversible and is referred to as “the primary switching system.” The additional switch phenotype, filament, has been identified and exhibits obviously filamentous morphology when grown on glycerol-containing medium. Several unique characteristics of the filamentous phenotype suggest that switching from or to this phenotype poses as a second yeast-filament switching system. The yeast-filament switch is nonheritable and temperature-dependent. Low temperatures favor the filamentous phenotype, whereas high temperatures promote filament-yeast transition. We further demonstrated that numerous aspects of the distinct cell types differ in numerous biological aspects, including their high temperature response, specific gene expression, CuSO4 tolerance, secreted aspartyl protease (SAP) activity, and virulence. Therefore, transition among the three phenotypes could enable C. haemulonii to rapidly adapt to, survive, and thrive in certain host niches, thereby contributing to its virulence. IMPORTANCE The capacity to switch between distinct cell types, known as phenotypic switching, is a common strategy adopted by Candida species to adapt to diverse environments. Despite considerable studies on phenotypic plasticity of various Candida species, Candida haemulonii is considered to be incapable of phenotypic switching or filamentous growth. Here, we report and describe filamentation and three distinct phenotypes (white, pink, and filament) in C. haemulonii. The three cell types differ in cellular and colony appearance, gene expression profiles, CuSO4 tolerance, and virulence. C. haemulonii cells switch heritably and reversibly between white and pink cell types, which is referred to as the “primary switching system.” Switching between pink and filamentous phenotypes is nonheritable and temperature-dependent, representing a second switching system. As in other Candida species, switching among distinct morphological types may provide C. haemulonii with phenotypic plasticity for rapid responses to the changing host environment, and may contribute to its virulence.

Wickerhamomyces anomalus is an emerging pathogen, which has been associated with clonal outbreaks and poor clinical outcomes. Despite being an important emerging yeasts species, our understanding concerning the microbiological and clinical characteristics of infections due to this species is limited. Herein, we are reporting a retrospective analysis of fungemia patients with W. anomalus from a 2,100-bed hospital in Shanghai during 2014–2016. Moreover, we conducted an extensive literature review to gain a deeper clinical and microbiological insights. Detailed clinical data were recorded. Antifungal susceptibility testing (AFST) followed CLSI M27-A3, and isolates were identified using MALDI-TOF MS. In total, 13 patients were identified with a mortality rate of 38.5% (5/13). Central venous catheter (CVC), broad-spectrum antibiotic therapy, total parenteral nutrition (TPN), surgery, and mechanical ventilation were the most frequently observed risk factors. Eight patients (61.5%) experienced mixed bacterial/Candida bloodstream infections, and four patients developed mixed candidemia (MC). W. anomalus isolates showed high minimum inhibitory concentrations (MICs) against all azoles tested and flucytosine, while AMB showed the highest in vitro activity. Azoles were used for 84.6% (11/13) of the cases, while 36.4% (4/11) of them died. When combining with the AFST data and the literature review, our study highlights the poor efficacy of azoles and optimal efficacy of AMB and LAMB against infections caused by W. anomalus. In conclusion, our study highlights the emerging threat of W. anomalus affecting both neonates and adults. Furthermore, our results advocate the use of AMB formulations rather than azoles among patients infected with W. anomalus. Future studies are warranted to reach a definitive consensus regarding the utility of echinocandins among such patients.

It is highly desired to explore cheap, non-toxic transition metals catalysts for semihydrogenation of acetylene. Here, isolated Cu atoms anchored onto a defective nanodiamond-graphene support exhibit robust catalytic performance in acetylene semihydrogenation in comparison with supported Cu clusters.

The general synthesis of single atom catalysts (SACs) is of broad interest to chemists but remains a formidable challenge. Here, with the precursor-dilution strategy, the authors successfully prepare 24 different SACs and the Pt SACs exhibit superior chemo- and regio-selectivity in hydrogenation.

Summary: Single-atom catalysts (SACs) have attracted broad interest recently due to their superior catalytic properties. However, a facile fabrication method for the large-scale synthesis of SACs is still in demand. This study reports a mechanochemical approach for the mass production of noble metal SACs. The successful formation of atomically dispersed palladium species on zinc oxide (Pd1/ZnO) was verified by aberration-corrected high-angle annular dark-field scanning transmission electron microscopy and X-ray absorption spectroscopy. Furthermore, our method exhibited little scaling-up effect on the mass production of Pd1/ZnO at ranges of 10–1,000 g, in which the catalyst structure and catalytic performance were retained. Meanwhile, the versatility of this approach was demonstrated by the large-scale fabrication of Rh and Ru SACs, and Pd1/Cu single-atom alloys. Thus, this promising strategy provides the potential for cost-effective mass production of SACs and subsequently may open a window for their industrial application.

Assembling Ln3+(HPBAn) (Ln = Eu or Tb, HPBA = N-(2-pyridinyl)benzoylacetamide) in the cavities of zeolite Y (ZY) via the “ship-in-a-bottle„ strategy leads to the formation of novel luminescent composite, Ln(HPBAn)@ZY, whose luminescence can be easily modulated by ammonia on the basis of the energy level variation of HPBA after deprotonation process. Additionally the bimetallic complex doping sample, Eu0.5Tb0.5(HPBAn)@ZY, show great potential as self-referencing luminescent sensor for detecting low ammonia concentration of 10−12⁻0.25 wt%.

Porous silicon nitride ceramics are attracting extensive attention due to its high strength and low dielectric loss. However, further strength enhancement at elevated temperatures is hindered by its intergranular phase, forming from sintering additives. This paper describes the fabrication of porous silicon nitride ceramic materials, by using a replacement method of carbothermal nitridation. The initial samples which were obtained from the sintering of mixed powder consisted of 95 wt% Si3N4 and 5 wt% Y2O3. After the removal of the oxide intergranular phase and the infiltration of mixtures of phenolic resins and silica sols, carbothermal nitridation process was carried out at 1550 °C for 2 h under nitrogen. X-ray diffraction and microstructural analysis revealed a complete replacement of oxide intergranular phases by the newly formed Si3N4 intergranular phase. The unmodified ceramic exhibited lower flexural strength at 1400 °C, which was only 50% of the room-temperature strength. Although the modified ceramic attained a slightly lower flexural strength at room temperature after the replacement of intergranular phase, its strength measured at 1400 °C could attain 90% of room-temperature strength. [ABSTRACT FROM AUTHOR]