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Due to the transboundary nature of air pollutants, a province's efforts to improve air quality can reduce PM2.5 concentration in the surrounding area. The inter-provincial PM2.5 pollution transport could bring great challenges to related environmental management work, such as financial fund allocation and subsidy policy formulation. Herein, we examined the transport characteristics of PM2.5 pollution across provinces in 2013 and 2020 via chemical transport modeling and then monetized inter-provincial contributions of PM2.5 improvement based on pollutant emission control costs. We found that approximately 60% of the PM2.5 pollution was from local sources, while the remaining 40% originated from outside provinces. Furthermore, about 1011 billion RMB of provincial air pollutant abatement costs contributed to the PM2.5 concentration decline in other provinces during 2013–2020, accounting for 41.2% of the total abatement costs. Provinces with lower unit improvement costs for PM2.5, such as Jiangsu, Hebei, and Shandong, were major contributors, while Guangdong, Guangxi, and Fujian, bearing higher unit costs, were among the main beneficiaries. Our study identifies provinces that contribute to air quality improvement in other provinces, have high economic efficiency, and provide a quantitative framework for determining inter-provincial compensations. This study also reveals the uneven distribution of pollution abatement costs (PM2.5 improvement/abatement costs) due to transboundary PM2.5 transport, calling for adopting inter-provincial economic compensation policies. Such mechanisms ensure equitable cost-sharing and effective regional air quality management.

[Objective] Due to continuous changes in the operating conditions of metro lines, abnormal vibrations between wheel and rail s occasionally occur, leading to fractures in the suspension components at the bogie axle-end and affecting the safety of train operation. Therefore, it is essential to conduct research on the fracture mechanisms of the axle-end suspension components. [Method] Taking the grounding terminals of bogie axle-end grounding cables of a metro train as an example, through line testing and data analysis, the reasons for grounding terminal fractures are analyzed, resolution measures involving mis-frequency design is proposed, and the feasibility is verified through on-site testing. [Result & Conclusion] The proposed resolution measures can reduce the stress at the grounding terminals from 90 MPa to approximately 30 MPa, significantly improving the stress state of the grounding terminals and enhancing their fatigue life.

China is now confronting the intertwined challenges of air pollution and climate change. Given the high synergies between air pollution abatement and climate change mitigation, the Chinese government is actively promoting synergetic control of these two issues. The Synergetic Roadmap project was launched in 2021 to track and analyze the progress of synergetic control in China by developing and monitoring key indicators. The Synergetic Roadmap 2022 report is the first annual update, featuring 20 indicators across five aspects: synergetic governance system and practices, progress in structural transition, air pollution and associated weather-climate interactions, sources, sinks, and mitigation pathway of atmospheric composition, and health impacts and benefits of coordinated control. Compared to the comprehensive review presented in the 2021 report, the Synergetic Roadmap 2022 report places particular emphasis on progress in 2021 with highlights on actions in key sectors and the relevant milestones. These milestones include the proportion of non-fossil power generation capacity surpassing coal-fired capacity for the first time, a decline in the production of crude steel and cement after years of growth, and the surging penetration of electric vehicles. Additionally, in 2022, China issued the first national policy that synergizes abatements of pollution and carbon emissions, marking a new era for China's pollution-carbon co-control. These changes highlight China's efforts to reshape its energy, economic, and transportation structures to meet the demand for synergetic control and sustainable development. Consequently, the country has witnessed a slowdown in carbon emission growth, improved air quality, and increased health benefits in recent years.

Abstract Metal additive manufacturing (AM) is gaining traction but raises worker health concerns due to micron‐sized powders, including fine inhalable particles. This study explored particle and surface characteristics, electrochemical properties, metal release in artificial lysosomal fluid (ALF), and potential toxicity of virgin and sieved virgin Fe‐based powders, stainless steel (316L), Fe, and two tooling steels. Virgin particles ranged in size from 1 to 100 µm, while sieved particles were within the respirable size range (

Abstract The increasing use of additive manufacturing (AM) techniques (e.g., 3D-printing) offers many advantages but at the same time presents some challenges. One concern is the possible exposure and health risk related to metal containing particles of different sizes. Using the nickel-based alloys Hastelloy X (HX) and Inconel 939 (IN939) as a case, the aim of this cross-disciplinary study was to increase the understanding on possible health hazards and exposure. This was done by performing in-depth characterization of virgin, reused and condensate powders, testing in vitro toxicity (cytotoxicity, genotoxicity, oxidative stress), and measuring occupational airborne exposure. The results showed limited metal release from both HX and IN939, and slightly different surface composition of reused compared to virgin powders. No or small effects on the cultured lung cells were observed when tested up to 100 µg/mL. Particle background levels in the printing facilities were generally low, but high transient peaks were observed in relation to sieving. Furthermore, during post processing with grinding, high levels of nanoparticles (> 100,000 particles/cm3) were noted. Urine metal levels in AM operators did not exceed biomonitoring action limits. Future studies should focus on understanding the toxicity of the nanoparticles formed during printing and post-processing.

ABSTRACTThe persistent pandemic of coronavirus disease in 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently poses a major infectious threat to public health around the world. COVID-19 is an infectious disease characterized by strong induction of inflammatory cytokines, progressive lung inflammation, and potential multiple organs dysfunction. SARS-CoV-2 infection is closely related to the innate immune system and adaptive immune system. Dendritic cells (DCs), as a “bridge” connecting innate immunity and adaptive immunity, play many important roles in viral diseases. In this review, we will pay special attention to the possible mechanism of dendritic cells in human viral transmission and clinical progression of diseases, as well as the reduction and dysfunction of DCs in severe SARS-CoV-2 infection, so as to understand the mechanism and immunological characteristics of SARS-CoV-2 infection.

Glutamate receptor-like genes (GLRs) are essential in the growth and development of plants and many physiological and biochemical processes; however, related information in soybean is lacking. In this study, 105 GLRs, including 67 Glycine soja and 38 Glycine max GLRs, were identified and divided into two clades (Clades II and III) according to their phylogenetic relationships. GLR members in the same branch had a relatively conservative motif composition and genetic structure. Furthermore, the soybean GLR family mainly experienced purification selection during evolution. Cis-acting element analysis, gene ontology, and Kyoto Encyclopedia of Genes and Genomic annotations indicated the complexity of the gene regulation and functional diversity of the soybean GLR. Moreover, transcriptome data analysis showed that these GLRs had different expression profiles in different tissues, and Clade III members had higher and more common expression patterns. Additionally, the expression profiles under jasmonic acid treatment and salt stress indicate that the GLR participated in the jasmonic acid signaling pathway and plays a role in salt treatment. This study provides information for a comprehensive understanding of the soybean GLR family and a reference for further functional research and genetic improvement.

It is well recognized that carbon dioxide and air pollutants share similar emission sources so that synergetic policies on climate change mitigation and air pollution control can lead to remarkable co-benefits on greenhouse gas reduction, air quality improvement, and improved health. In the context of carbon peak, carbon neutrality, and clean air policies, this perspective tracks and analyzes the process of the synergetic governance of air pollution and climate change in China by developing and monitoring 18 indicators. The 18 indicators cover the following five aspects: air pollution and associated weather-climate conditions, progress in structural transition, sources, inks, and mitigation pathway of atmospheric composition, health impacts and benefits of coordinated control, and synergetic governance system and practices. By tracking the progress in each indicator, this perspective presents the major accomplishment of coordinated control, identifies the emerging challenges toward the synergetic governance, and provides policy recommendations for designing a synergetic roadmap of Carbon Neutrality and Clean Air for China.

AbstractStephania cepharantha Hayata (S. cepharantha) is a common folk medicine herb in China with many therapeutic activities. This study used Illumina sequencing technology to construct a circular chloroplast genome map and compared it with that of other Stephania species. The genome of S. cepharantha is 158,052 bp in length, including a large single-copy region of 88,770 bp, a small single-copy region of 19,760 bp, and two reverse repeat regions of 49,522 bp. The genome encodes eight ribosomal ribonucleic acid (RNA) genes, 37 transfer RNA genes, and 85 protein-coding genes. Nucleotide variation analysis revealed that six highly variable regions of Stephania can be used as potential molecular markers for taxonomic research and evolutionary analysis. This study is the first chloroplast genome report on S. cepharantha, and it provides rich and valuable genetic information for understanding the evolutionary relationships and population inheritance of the species.

Although recent studies show the hypolipidemic effect of Rosa roxburghii, however reported findings are contradictory. Using meta-analysis, we aimed to explore the effect of R. roxburghii on blood lipid levels. An extensive literature search was performed to investigate the effect of R. roxburghii on various lipid indexes. The results showed that R. roxburghii fruit can significantly reduce total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels and increase high-density lipoprotein cholesterol levels. R. roxburghii fruit can therefore be used to regulate blood lipid concentrations and it can be considered a valuable adjuvant therapy for blood lipid control. However, this needs confirmation through additional research.

Deep Neural Network (DNN)-based point cloud semantic segmentation has presented significant breakthrough using large-scale labeled aerial laser point cloud datasets. However, annotating such large-scaled point clouds is time-consuming. Self-Supervised Learning (SSL) is a promising approach to this problem by pre-training a DNN model utilizing unlabeled samples followed by a fine-tuned downstream task involving very limited labels. The traditional contrastive learning for point clouds selects the hardest negative samples by solely relying on the distance between the embedded features derived from the learning process, potentially evolving some negative samples from the same classes to reduce the contrastive learning effectiveness. This work proposes a hard-negative sample-aware self-supervised contrastive learning algorithm to pre-train the model for semantic segmentation. We designed a k-means clustering-based Absolute Positive And Negative samples (AbsPAN) strategy to filter the possible false-negative samples. Experiments on two typical ALS benchmark datasets demonstrate that the proposed method is more appealing than supervised training schemes without pre-training. Especially when the labels are severely inadequate (10% of the ISPRS training set), the results obtained by the proposed HAVANA method still exceed 94% of the supervised paradigm performance with full training set.

The segmentation of airborne laser scanning (ALS) point clouds remains a challenge in remote sensing and photogrammetry. Deep learning methods, such as KPCONV, have proven effective on various datasets. However, the rigid convolutional kernel strategy of KPCONV limits its potential use for 3D object segmentation due to its uniform approach. To address this issue, we propose an Integrated Point Convolution (IPCONV) based on KPCONV, which utilizes two different convolution kernel point generation strategies, one cylindrical and one a spherical cone, for more efficient learning of point cloud data features. We propose a customizable Multi-Shape Neighborhood System (MSNS) to balance the relationship between these convolution kernel point generations. Experiments on the ISPRS benchmark dataset, LASDU dataset, and DFC2019 dataset demonstrate the validity of our method.

Masked image modeling (MIM) is a learning method in which the unmasked components of the input are utilized to learn and predict the masked signal, enabling learning from large amounts of unannotated data. However, due to the scale diversity and complexity of features in remote sensing images (RSIs), existing MIMs face two challenges in the RSI scene classification task: (1) If the critical local patches of small-scale objects are randomly masked out, the model will be unable to learn its representation. (2) The reconstruction of MIM relies on the visible local contextual information surrounding the masked regions and overemphasizing this local information will potentially lead the model to disregard the global semantic information of the input RSI. Regarding the above considerations, we proposed a global semantic integrated self-distilled complementary masked image model (GSC-MIM) for RSI scene classification. To prevent information loss, we proposed an information-preserved complementary masking strategy (IPC-Masking), which generates two complementary masked views for the same image to resolve the problem of masking critical areas of small-scale objects. To incorporate global information into the MIM pre-training process, we proposed the global semantic distillation strategy (GSD). Specifically, we introduced an auxiliary network pipeline to extract the global semantic information from the full input RSI and transfer the knowledge to the MIM by self-distillation. The proposed GSC-MIM is validated on three publicly available datasets of AID, NWPU-RESISC45, and UC-Merced Land Use, and the results show that the proposed method's Top-1 accuracy surpasses the baseline approaches in three datasets by up to 4.01, 3.87, and 5.26%, respectively.

Since 2021, cobalt (Co) is in Europe classified as carcinogen in quantities exceeding 0.1 wt-%. This affects nickel-rich stainless steels, which contain about 0.2 wt-% Co impurities. Previous findings show the bioaccessibility of Co in stainless steel to be primarily determined by the corrosion resistance. It has been unclear whether Co is distributed heterogeneously in the alloy and the outermost surface and whether a specific location would pose a risk for Co release under specific exposure conditions. This study aimed at locating Co in stainless steel 316L (0.2 wt-% Co) surfaces prior to and after exposure to different synthetic body fluids for 24 h at 37 °C. Time-of-flight secondary ion mass spectrometry (ToF-SIMS), X-ray photoelectron spectroscopy (XPS), and inductively coupled plasma mass spectrometry (ICPMS) investigated the location of Co in the surface oxide and extent of release along with other metals (iron, chromium, nickel, and manganese) into synthetic biological fluids (gastric fluid, pH 1.5; lysosomal fluid, pH 4.5; phosphate buffered saline-PBS, pH 7.4). Co was homogeneously distributed along with metallic nickel beneath the surface oxide and co-released with other metals upon surface reformation and passivation. Exposure in PBS resulted in the incorporation of both Co and phosphate in the oxide.

The looper tension control system of hot strip mills is a typical multi-agent system, and the coupling effects among the agents are strong. However,it is difficult for us to establish the accurate coupling model for the looper tension control system. In this study, a distributed control strategy is proposed for the looper tension control system. With the subspace identification method, the local measurement of the looper control system and the information of its neighbors are used directly to develop the consensus control protocol without any knowledge of the looper tension system dynamics. The sufficient conditions for the consensus of multi-agent system with the proposed control protocol are proposed. In addition, a consensus control protocol with communication time delay is presented. Finally simulations are performed to verify the effectiveness of the control strategy.

The widespread use of silica nanoparticles (SiNPs) has increased the risk of human exposure, which raised concerns about their adverse effects on human health, especially the reproductive system. Previous studies have shown that SiNPs could cause damage to reproductive organs, but the specific mechanism is still unclear. In this study, to investigate the underlying mechanism of male reproductive toxicity induced by SiNPs, 40 male mice at the age of 8 weeks were divided into two groups and then intraperitoneally injected with vehicle control or 10 mg/kg SiNPs per day for one week. The results showed that SiNPs could damage testicular structure, perturb spermatogenesis and reduce serum testosterone levels, leading to a decrease in sperm quality and quantity. In addition, the ROS level in the testis of exposed mice was significantly increased, followed by imbalance of the oxidative redox status. Further study revealed that exposure to SiNPs led to cell cycle arrest and apoptosis, as shown by downregulation of the expression of positive cell cycle regulators and the activation of TNF-α/TNFR Ⅰ-mediated apoptotic pathway. The results demonstrated that SiNPs could cause testicles injure via inducing oxidative stress and DNA damage which led to cell cycle arrest and apoptosis, and thereby resulting in spermatogenic dysfunction

Additive manufacturing (AM) or industrial 3D printing uses cutting-edge technologies and materials to produce a variety of complex products. However, the effects of the unintentionally emitted AM (nano)particles (AMPs) on human cells following inhalation, require further investigations. The physicochemical characterization of the AMPs, extracted from the filter of a Laser Powder Bed Fusion (L-PBF) 3D printer of iron-based materials, disclosed their complexity, in terms of size, shape, and chemistry. Cell Painting, a high-content screening (HCS) assay, was used to detect the subtle morphological changes elicited by the AMPs at the single cell resolution. The profiling of the cell morphological phenotypes, disclosed prominent concentration-dependent effects on the cytoskeleton, mitochondria, and the membranous structures of the cell. Furthermore, lipidomics confirmed that the AMPs induced the extensive membrane remodeling in the lung epithelial and macrophage co-culture cell model. To further elucidate the biological mechanisms of action, the targeted metabolomics unveiled several inflammation-related metabolites regulating the cell response to the AMP exposure. Overall, the AMP exposure led to the internalization, oxidative stress, cytoskeleton disruption, mitochondrial activation, membrane remodeling, and metabolic reprogramming of the lung epithelial cells and macrophages. We propose the approach of integrating Cell Painting with metabolomics and lipidomics, as an advanced nanosafety methodology, increasing the ability to capture the cellular and molecular phenotypes and the relevant biological mechanisms to the (nano)particle exposure.

Hazard classification of metal alloys is today generally based on their bulk content, an approach that seldom reflects the extent of metal release for a given environment. Such information can instead be achieved via bioelution testing under simulated physiological conditions. The use of bioelution data instead of bulk contents would hence refine the current hazard classification of alloys and enable grouping. Bioelution data have been generated for nickel (Ni) and cobalt (Co) released from several stainless steel grades, one low-alloyed steel, and Ni and Co metals in synthetic sweat, saliva and gastric fluid, for exposure periods from 2 to 168 h. All stainless steel grades with bulk contents of 0.11–10 wt% Ni and 0.019–0.24 wt% Co released lower amounts of Ni (up to 400-fold) and Co (up to 300-fold) than did the low-alloyed steel (bulk content: 0.034% Ni, 0.015% Co). They further showed a relative bioaccessibility of Ni and Co considerably less than 1, while the opposite was the case for the low-alloyed steel. Surface oxide- and electrochemical corrosion investigations explained these findings in terms of the high passivity of the stainless steels related to the Cr(III)-rich surface oxide that readily adapted to the fluid acidity and chemistry.

Brain–computer interface (BCI) research has attracted worldwide attention and has been rapidly developed. As one well-known non-invasive BCI technique, electroencephalography (EEG) records the brain’s electrical signals from the scalp surface area. However, due to the non-stationary nature of the EEG signal, the distribution of the data collected at different times or from different subjects may be different. These problems affect the performance of the BCI system and limit the scope of its practical application. In this study, an unsupervised deep-transfer-learning-based method was proposed to deal with the current limitations of BCI systems by applying the idea of transfer learning to the classification of motor imagery EEG signals. The Euclidean space data alignment (EA) approach was adopted to align the covariance matrix of source and target domain EEG data in Euclidean space. Then, the common spatial pattern (CSP) was used to extract features from the aligned data matrix, and the deep convolutional neural network (CNN) was applied for EEG classification. The effectiveness of the proposed method has been verified through the experiment results based on public EEG datasets by comparing with the other four methods.

Abstract Background Diabetes is a chronic disease, and it could affect both health and quality of life (QOL). A lot of studies have reported some predictors of QOL of type 2 diabetes patients. While their results were not completely consistent. So the aim of our study was finding out the related factors (including characteristics related to the disease, life styles and mental health factors) of QOL of type 2 diabetes patients. Methods We searched Cochrane library, EmBase, PubMed and CNKI databases for published studies that evaluated the related factors of QOL of type 2 diabetes patients by using a proper statistic method and had effect sizes (OR or β) and 95% confidence intervals from January 1st 2000 to May 31st 2016. Any study types were acceptable, and we excluded the reviews, letters, editorials and pooled analyses. The data were analyzed using STATA software (Version 12.0; Stata Corporation). Effect sizes and 95% confidence intervals were calculated to evaluate the relationship between these factors and QOL. Results Eighteen studies were included into our systematic review and meta-analysis, totaling 57,109 type 2 diabetes patients. Do more physical exercises (The pooled ORs ranged from 0.635 to 0.825 for different scales, less than 1.00), glucose check more frequently [pooled OR (95%CI): 0.175 (0.041, 0.756)] were associated with a better QOL. Presence of complications (The pooled ORs ranged from 1.462 to 3.038 for different scales, more than 1.00), presence of hypertension [pooled OR (95%CI): 1.389 (1.173, 1644)], longer duration of diabetes [pooled OR (95%CI): 1.865 (1.088, 3.197)], diet with more red meat [pooled OR (95%CI): 2.085 (1.063, 4.089)] and depression (The pooled ORs ranged from 3.003 to 11.473 for different scales, higher than 1.00) were associated with a worse QOL. Conclusion The results of this study show that physical exercise, glucose check frequently, complications, hypertension, duration of diabetes, diet with more red meat, and depression were associated with the QOL of type 2 diabetes patients.

ObjectiveThis study aimed to identify the local levels of vulnerability among patients with Type-II diabetes (T2DM) in Tianjin. The study was aimed at curbing the rise of T2DM in cities.Methods229 participants living with T2DM were purposively sampled from hospitals in Tianjin. Collected data were coded and analysed following well-established thematic analysis principles.ResultsTwelve themes involving 29 factors were associated with diabetes patients' vulnerability: 1. Financial constraints (Low Income, Unemployment, No Medical Insurance/Low ratio reimbursement); 2. Severity of disease (Appearance of symptoms, complications, co-morbidities, high BMI, poor disease control); 3. Health literacy (No/Low/Wrong knowledge of health literacy); 4. Health beliefs (Perceived diabetes indifferently, Passively Acquire Health Knowledge, Distrust of primary health services); 5. Medical environment (Needs not met by Medical Services); 6. Life restrictions (Daily Life, Occupational Restriction); 7. Lifestyle change (Adhering to traditional or unhealthy diet, Lack of exercise, Low-quality sleep); 8. Time poverty (Healthcare-seeking behaviours were limited by work, Healthcare-seeking behaviours were limited by family issues); 9. Mental Condition (Negative emotions towards diabetes, Negative emotions towards life); 10. Levels of Support (Lack of community support, Lack of support from Friends and Family, Lack of Social Support); 11. Social integration (Low Degree of Integration, Belief in Suffering Alone); 12. Experience of transitions (Diet, Dwelling Environment).ConclusionBased on our findings, specific interventions targeting individual patients, family, community and society are needed to improve diabetes control, as well as patients' mental health care and general living conditions.

Change in future climate will either expand, contract or shift the climatic niche of many species and this could lead to shifting of their geographical ranges. Prediction of suitable cultivation regions through modeling has evolved as a useful tool for the assessment of habitat suitability and resource conservation to protect medicinal plants. We modelled current and future distribution of C. tinctorius based on three representative concentration pathways (RCP2.6, RCP4.5 and RCP8.5) for the year 2050s and 2070s using a maximum entropy model (MaxEnt) and geographical information system (GIS) in China. For modeling procedure 99 occurrence records and 11 Worldclim environmental factors was used in this paper. The results show that the area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate model performance. All of the AUCs were greater than 0.970, thereby placing these models in the “Excellent” category. The jackknife test also showed that maximum temperature in March (tmax3), maximum temperature in February (tmax2), maximum temperature in November (tmax11), precipitation in July (prec7) and precipitation in August (prec8) were the main variables. From the area of current distribution, of the total 6276666.77 km2 (65.36%) area, 27.28% area (2619895.88 km2) was highly suitable for safflower in China, and the highly suitable area (with suitability between 66 and 100) was mainly concentrated in Sichuan (2.74%), Yunnan (2.09%), Shaanxi (1.82%), Hubei (1.76%), Guizhou (1.66%), Henan (1.66%) and Hunan (1.64%). Xinjiang was the largest suitable area, which accounts for 9.70%. It was worth noting, realized niche was little planting in Sichuan province due to market and economic price factors, social factors and other factors. Compared to the current distribution, the total area of the poorly suitable regions and moderately suitable regions for safflower under the three RCPs (RCP2.6, RCP4.5 and RCP8.5) would increase in 2050s and 2070s. However, the total area of the highly suitable regions under the three RCPs (RCP2.6, RCP4.5 and RCP8.5) in 2050s and two RCPs (RCP2.6 and RCP4.5) in 2070s would decrease. This research would provide theoretical suggestions for the protection, cultivation management, and sustainable utilization of C. tinctorius resources to face the challenge of global climate change. Keywords: C. tinctorius, MaxEnt model, Climate change, ArcGIS, Suitable habitat

Terahertz absorber has attracted much attention. However, most of them have complex structures and narrow bandwidth. Here, a wideband terahertz metasurface absorber based on Mie resonance is demonstrated. The metasurface absorber is prepared by combining four dielectric resonators with different permittivity values into a single unit cell. The absorption of the wideband metasurface absorber goes beyond 80% from 8.37 to 8.60 THz, showing wideband absorption performance. In addition, the center frequency of the wideband metasurface absorber can be tuned by the size and permittivity of the dielectric resonators, which makes the proposed absorber suitable for applications in wideband terahertz devices.

We mainly investigated the effect of the valence state of photorefractive resistant elements on the photorefractive properties of codoped crystals, taking the Zn and Mo codoped LiNbO3 (LN:Mo,Zn) crystal as an example. Especially, the response time and photorefractive sensitivity of 7.2 mol% Zn and 0.5 mol% Mo codoped with LiNbO3 (LN:Mo,Zn7.2) crystal are 0.65 s and 4.35 cm/J at 442 nm, respectively. The photorefractive properties of the LN:Mo,Zn crystal are similar to the Mg and Mo codoped LiNbO3 crystal, which are better than the Zr and Mo codoped LiNbO3 crystal. The results show that the valence state of photorefractive resistant ions is an important factor for the photorefractive properties of codoped crystals and that the LN:Mo,Zn7.2 crystal is another potential material with fast response to holographic storage.

RNAi is a ubiquitous pathway that serves central functions throughout eukaryotes, including maintenance of genome stability and repression of transposon expression and movement. However, a number of organisms have lost their RNAi pathways, including the model yeast Saccharomyces cerevisiae, the maize pathogen Ustilago maydis, the human pathogen Cryptococcus deuterogattii, and some human parasite pathogens, suggesting there may be adaptive benefits associated with both retention and loss of RNAi. By comparing the RNAi-deficient genome of the Pacific Northwest Outbreak C. deuterogattii strain R265 with the RNAi-proficient genomes of the Cryptococcus pathogenic species complex, we identified a set of conserved genes that were lost in R265 and all other C. deuterogattii isolates examined. Genetic and molecular analyses reveal several of these lost genes play roles in RNAi pathways. Four novel components were examined further. Znf3 (a zinc finger protein) and Qip1 (a homolog of N. crassa Qip) were found to be essential for RNAi, while Cpr2 (a constitutive pheromone receptor) and Fzc28 (a transcription factor) are involved in sex-induced but not mitosis-induced silencing. Our results demonstrate that the mitotic and sex-induced RNAi pathways rely on the same core components, but sex-induced silencing may be a more specific, highly induced variant that involves additional specialized or regulatory components. Our studies further illustrate how gene network polymorphisms involving known components of key cellular pathways can inform identification of novel elements and suggest that RNAi loss may have been a core event in the speciation of C. deuterogattii and possibly contributed to its pathogenic trajectory.

ABSTRACT Cryptococcosis is an infectious disease of global significance for which new therapies are needed. Repurposing previously developed drugs for new indications can expedite the translation of new therapies from bench to beside. Here, we characterized the anti-cryptococcal activity and antifungal mechanism of estrogen receptor antagonists related to the breast cancer drugs tamoxifen and toremifene. Tamoxifen and toremifene are fungicidal and synergize with fluconazole and amphotericin B in vitro. In a mouse model of disseminated cryptococcosis, tamoxifen at concentrations achievable in humans combines with fluconazole to decrease brain burden by ~1 log10. In addition, these drugs inhibit the growth of Cryptococcus neoformans within macrophages, a niche not accessible by current antifungal drugs. Toremifene and tamoxifen directly bind to the essential EF hand protein calmodulin, as determined by thermal shift assays with purified C. neoformans calmodulin (Cam1), prevent Cam1 from binding to its well-characterized substrate calcineurin (Cna1), and block Cna1 activation. In whole cells, toremifene and tamoxifen block the calcineurin-dependent nuclear localization of the transcription factor Crz1. A large-scale chemical genetic screen with a library of C. neoformans deletion mutants identified a second EF hand-containing protein, which we have named calmodulin-like protein 1 (CNAG_05655), as a potential target, and further analysis showed that toremifene directly binds Cml1 and modulates its ability to bind and activate Cna1. Importantly, tamoxifen analogs (idoxifene and methylene-idoxifene) with increased calmodulin antagonism display improved anti-cryptococcal activity, indicating that calmodulin inhibition can be used to guide a systematic optimization of the anti-cryptococcal activity of the triphenylethylene scaffold. IMPORTANCE Worldwide, cryptococcosis affects approximately 1 million people annually and kills more HIV/AIDS patients per year than tuberculosis. The gold standard therapy for cryptococcosis is amphotericin B plus 5-flucytosine, but this regimen is not readily available in regions where resources are limited and where the burden of disease is highest. Herein, we show that molecules related to the breast cancer drug tamoxifen are fungicidal for Cryptococcus and display a number of pharmacological properties desirable for an anti-cryptococcal drug, including synergistic fungicidal activity with fluconazole in vitro and in vivo, oral bioavailability, and activity within macrophages. We have also demonstrated that this class of molecules targets calmodulin as part of their mechanism of action and that tamoxifen analogs with increased calmodulin antagonism have improved anti-cryptococcal activity. Taken together, these results indicate that tamoxifen is a pharmacologically attractive scaffold for the development of new anti-cryptococcal drugs and provide a mechanistic basis for its further optimization.

ABSTRACT Malassezia commensal yeasts are associated with a number of skin disorders, such as atopic eczema/dermatitis and dandruff, and they also can cause systemic infections. Here we describe the 7.67-Mbp genome of Malassezia sympodialis, a species associated with atopic eczema, and contrast its genome repertoire with that of Malassezia globosa, associated with dandruff, as well as those of other closely related fungi. Ninety percent of the predicted M. sympodialis protein coding genes were experimentally verified by mass spectrometry at the protein level. We identified a relatively limited number of genes related to lipid biosynthesis, and both species lack the fatty acid synthase gene, in line with the known requirement of these yeasts to assimilate lipids from the host. Malassezia species do not appear to have many cell wall-localized glycosylphosphatidylinositol (GPI) proteins and lack other cell wall proteins previously identified in other fungi. This is surprising given that in other fungi these proteins have been shown to mediate interactions (e.g., adhesion and biofilm formation) with the host. The genome revealed a complex evolutionary history for an allergen of unknown function, Mala s 7, shown to be encoded by a member of an amplified gene family of secreted proteins. Based on genetic and biochemical studies with the basidiomycete human fungal pathogen Cryptococcus neoformans, we characterized the allergen Mala s 6 as the cytoplasmic cyclophilin A. We further present evidence that M. sympodialis may have the capacity to undergo sexual reproduction and present a model for a pseudobipolar mating system that allows limited recombination between two linked MAT loci. IMPORTANCE Malassezia commensal yeasts are associated with a number of skin disorders. The previously published genome of M. globosa provided some of the first insights into Malassezia biology and its involvement in dandruff. Here, we present the genome of M. sympodialis, frequently isolated from patients with atopic eczema and healthy individuals. We combined comparative genomics with sequencing and functional characterization of specific genes in a population of clinical isolates and in closely related model systems. Our analyses provide insights into the evolution of allergens related to atopic eczema and the evolutionary trajectory of the machinery for sexual reproduction and meiosis. We hypothesize that M. sympodialis may undergo sexual reproduction, which has important implications for the understanding of the life cycle and virulence potential of this medically important yeast. Our findings provide a foundation for the development of genetic and genomic tools to elucidate host-microbe interactions that occur on the skin and to identify potential therapeutic targets.

Introduction of DNA sequences into the genome often results in homology-dependent gene silencing in organisms as diverse as plants, fungi, flies, nematodes, and mammals. We previously showed in Cryptococcus neoformans that a repeat transgene array can induce gene silencing at a high frequency during mating (∼50%), but at a much lower frequency during vegetative growth (∼0.2%). Here we report a robust asexual co-suppression phenomenon triggered by the introduction of a cpa1::ADE2 transgene. Multiple copies of the cpa1::ADE2 transgene were ectopically integrated into the genome, leading to silencing of the endogenous CPA1 and CPA2 genes encoding the cyclosporine A target protein cyclophilin A. Given that CPA1-derived antisense siRNAs were detected in the silenced isolates, and that RNAi components (Rdp1, Ago1, and Dcr2) are required for silencing, we hypothesize that an RNAi pathway is involved, in which siRNAs function as trans factors to silence both the CPA1 and the CPA2 genes. The silencing efficiency of the CPA1 and CPA2 genes is correlated with the transgene copy number and reached ∼90% in the presence of >25 copies of the transgene. We term this transgene silencing phenomenon asexual co-suppression to distinguish it from the related sex-induced silencing (SIS) process. We further show that replication protein A (RPA), a single-stranded DNA binding complex, is required for transgene silencing, suggesting that RPA might play a similar role in aberrant RNA production as observed for quelling in Neurospora crassa. Interestingly, we also observed that silencing of the ADE2 gene occurred at a much lower frequency than the CPA1/2 genes even though it is present in the same transgene array, suggesting that factors in addition to copy number influence silencing. Taken together, our results illustrate that a transgene induced co-suppression process operates during C. neoformans vegetative growth that shares mechanistic features with quelling.

The flipped classroom method has recently become popular in biology education. However, there is a lack of systematic and quantitative assessments on the efficiency of teaching medical microbiology using this novel approach. In this study, we performed a meta-analysis to explore the flipped classroom method's effects versus those of traditional lectures in medical microbiology education. Six electronic databases, including PubMed, Web of Science, ERIC, China National Knowledge Infrastructure (CNKI), Wanfang Data, and Chinese Scientific Journals Database, were searched to obtain relevant articles from the first publication on this topic up to March 2021. Study selection, data extraction, and quality estimations were conducted to analyse the effects. A total of 13 studies were included in this meta-analysis, with the results revealing a significantly improved effect within the flipped classroom model on students' theoretical [SMD = 0.56, 95% CI (0.28, 0.84), p < 0.0001] and practical examination scores [SMD = 0.70, 95% CI (0.19, 1.20), p = 0.007]. In terms of its teaching effects, the flipped classroom approach improves students' learning interest, self-study abilities, knowledge mastery, and satisfaction, but does exacerbate their learning burden. The flipped classroom method possesses multiple advantages when compared to traditional lectures in medical microbiology education, but does increase the burden experienced by students.