Competitive coordination assembly of light-degradable gold nanocluster-intercalated metal organic frameworks for photoresponsive drug release.

On-demand controlled drug release holds great promise for cancer therapy. Light-degradable nanocarriers have gained increasing attention for designing controllable drug delivery systems owing to their spatiotemporally controllable properties. Herein, a highly luminescent and light-degradable nanocarrier is constructed by intercalating glutathione-capped gold nanoclusters (AuNCs) into zeolitic imidazolate framework-8 (ZIF-8) via competitive coordination assembly, named AuNC@ZIF-8, for light-triggered drug release. Glutathione-capped AuNCs and 2-methylimidazole (MIm) competitively coordinated with Zn2+ to form AuNC@ZIF-8 using a one step process in an aqueous solution. Specifically, the obtained AuNC@ZIF-8 has a high quantum yield of 52.96% and displays a distinctive property of photolysis. Competitive coordination interactions within AuNC@ZIF-8 were evidenced by X-ray diffraction and X-ray photoelectron spectroscopy, in which Zn2+ strongly coordinated with the N of MIm and weakly coordinated with the carboxyl/amino groups in the glutathione of AuNCs. Under light irradiation, the Au-S bond in AuNCs breaks, enhancing the coordination ability between carboxyl/amino groups and Zn2+. This collapses the crystal structure of AuNC@ZIF-8 and causes subsequent fluorescence quenching. Additionally, AuNC@ZIF-8 is successfully employed as a luminescent nanocarrier of anticancer drugs to form drug-AuNC@ZIF-8, in which three typical anticancer drugs are selected due to different coordination interactions. The obtained smart drug-AuNC@ZIF-8 can be effectively internalized into HeLa cells and degraded in response to blue light, with negligible dark cytotoxicity and high light cytotoxicity. This study highlights the crucial role of competitive coordination interactions in synthesizing functional materials with fluorescence efficiency and photolytic properties.

Transcriptomic crosstalk between viral and host factors drives aberrant homeostasis of T-cell proliferation and cell death in HIV-infected immunological non-responders.

BACKGROUND: Immunological non-responders (INRs) among people living with HIV have inherently higher mortality and morbidity rates. The underlying immunological mechanisms whereby failure of immune reconstitution occurs in INRs require elucidation. METHOD: HIV-1 DNA and HIV-1 cell-associated RNA (CA-HIV RNA) quantifications were conducted via RT-qPCR. Transcriptome sequencing (RNA-seq), bioinformatics, and biological verifications were performed to discern the crosstalk between host and viral factors. Flow cytometry was employed to analyze cellular activation, proliferation, and death. RESULTS: HIV-1 DNA and CA-HIV RNA levels were observed to be significantly higher in INRs compared to immunological responders (IRs). Evaluation of CD4/CD8 ratios showed a significantly negative correlation with HIV-1 DNA in IRs, but not in INRs. Bioinformatics analyses and biological verifications showed IRF7/INF-α regulated antiviral response was intensified in INRs. PBMCs of INRs expressed significantly more HIV integrase-mRNA (p31) than IRs. Resting (CD4+CD69- T-cells) and activated (CD4+CD69+ T-cells) HIV-1 reservoir harboring cells were significantly higher in INRs, with the co-occurrence of significantly higher cellular proliferation and cell death in CD4+ T-cells of INRs. CONCLUSION: In INRs, the systematic crosstalk between the HIV-1 reservoir and host cells tends to maintain a persistent antiviral response-associated inflammatory environment, which drives aberrant cellular activation, proliferation, and death of CD4+ T-cells.

Novel histone post-translational modifications in Alzheimer's disease: current advances and implications.

Alzheimer's disease (AD) has a complex pathogenesis, and multiple studies have indicated that histone post-translational modifications, especially acetylation, play a significant role in it. With the development of mass spectrometry and proteomics, an increasing number of novel HPTMs, including lactoylation, crotonylation, ß-hydroxybutyrylation, 2-hydroxyisobutyrylation, succinylation, and malonylation, have been identified. These novel HPTMs closely link substance metabolism to gene regulation, and an increasing number of relevant studies on the relationship between novel HPTMs and AD have become available. This review summarizes the current advances and implications of novel HPTMs in AD, providing insight into the deeper pathogenesis of AD and the development of novel drugs.

ALKBH5-mediated upregulation of CPT1A promotes macrophage fatty acid metabolism and M2 macrophage polarization, facilitating malignant progression of colorectal cancer.

m6A modification has been studied in tumors, but its role in host anti-tumor immune response and TAMs polarization remains unclear. The fatty acid oxidation (FAO) process of TAMs is also attracting attention. A co-culture model of colorectal cancer (CRC) cells and macrophages was used to simulate the tumor microenvironment. Expression changes of m6A demethylase genes FTO and ALKBH5 were screened. ALKBH5 was further investigated. Gain-of-function experiments were conducted to study ALKBH5's effects on macrophage M2 polarization, CRC cell viability, proliferation, migration, and more. Me-RIP and Actinomycin D assays were performed to study ALKBH5's influence on CPT1A, the FAO rate-limiting enzyme. AMP, ADP, and ATP content detection, OCR measurement, and ECAR measurement were used to explore ALKBH5's impact on macrophage FAO level. Rescue experiments validated ALKBH5's mechanistic role in macrophage M2 polarization and CRC malignant development. In co-culture, CRC cells enhance macrophage FAO and suppress m6A modification in M2 macrophages. ALKBH5 was selected as the gene for further investigation. ALKBH5 mediates CPT1A upregulation by removing m6A modification, promoting M2 macrophage polarization and facilitating CRC development. These findings indicate that ALKBH5 enhances fatty acid metabolism and M2 polarization of macrophages by upregulating CPT1A, thereby promoting CRC development.

Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1.

Tumor-resident microbiota in breast cancer promote cancer initiation and malignant progression. However, targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail. Here, we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis (ETBF) was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy. ETBF, albeit at low biomass, secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance. Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein. NOD1 was highly expressed on ALDH+ breast cancer stem cells (BCSCs) and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation, thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs. NOD1 inhibition and ETBF clearance increases the chemosensitivity of breast cancer by impairing BCSCs.

Large-scale functional network connectivity mediates the association between nigral neuromelanin hypopigmentation and motor impairment in Parkinson's disease.

Neuromelanin hypopigmentation within substantia nigra pars compacta (SNc) reflects the loss of pigmented neurons, which in turn contributes to the dysfunction of the nigrostriatal and striato-cortical pathways in Parkinson's disease (PD). Our study aims to investigate the relationships between SN degeneration manifested by neuromelanin reduction, functional connectivity (FC) among large-scale brain networks, and motor impairment in PD. This study included 68 idiopathic PD patients and 32 age-, sex- and education level-matched healthy controls who underwent neuromelanin-sensitive magnetic resonance imaging (MRI), functional MRI, and motor assessments. SN integrity was measured using the subregional contrast-to-noise ratio calculated from neuromelanin-sensitive MRI. Resting-state FC maps were obtained based on the independent component analysis. Subsequently, we performed partial correlation and mediation analyses in SN degeneration, network disruption, and motor impairment for PD patients. We found significantly decreased neuromelanin within SN and widely altered inter-network FCs, mainly involved in the basal ganglia (BG), sensorimotor and frontoparietal networks in PD. In addition, decreased neuromelanin content was negatively correlated with the dorsal sensorimotor network (dSMN)-medial visual network connection (P = 0.012) and dSMN-BG connection (P = 0.004). Importantly, the effect of SN neuromelanin hypopigmentation on motor symptom severity in PD is partially mediated by the increased connectivity strength between BG and dSMN (indirect effect = - 1.358, 95% CI: - 2.997, - 0.147). Our results advanced our understanding of the interactions between neuromelanin hypopigmentation in SN and altered FCs of functional networks in PD and suggested the potential of multimodal metrics for early diagnosis and monitoring the response to therapies.

Theoretical study of the synergic relationships between the design parameters in energy-saving building design.

With the rapid development of the economy, people have increasingly higher requirements for the comfort of living spaces, and the result is the sharp increase in building energy consumption. Several design parameters influence living space comfort and building energy efficiency. Since the same design standard can include different design parameter combinations, synergic relationships may exist between these criteria for one case. Identifying these synergic relationships requires an inverse problem approach. This paper established a model by combining an improved genetic algorithm (IGA) and numerical calculation to determine the synergic design parameter relationships (e.g. the thermophysical building material properties and energy-saving factors). For [Formula: see text], the shading coefficient significantly influenced the linear function between the thermal conductivity and insulation thickness. In this case, the insulation thickness was exponentially related to the shading coefficient, while the thermal conductivity of the insulation material significantly impacted the synergic relationship. For [Formula: see text], the insulation thickness was a segmented function of the shading coefficient. The results verified that the proposed model was efficient and reliable for identifying the synergic relationships between energy-saving parameters. In engineering applications, designers can select the optimal design parameter combination based on the relationship curve between the parameters in this paper according to the local market conditions and specific design requirements.

The combined detection of hematological indicators is used for the differential diagnosis of colorectal cancer and benign-colorectal lesions.

OBJECTIVE: This article aims to investigate the clinical value of hemoglobin/red cell distribution width ratio (Hb/RDW), C-reactive protein/albumin ratio (CAR) and plateletcrit (PCT) combined with carcinoembryonic antigen (CEA) in colorectal cancer (CRC) auxiliary diagnosis. METHODS: We retrospectively analyzed in 718 subjects (212 with CRC, 209 with benign colorectal lesions (BCL), 111 with other cancers, and 186 healthy controls). RESULTS: The CAR, PCT, and CEA in the CRC group were higher than those in the BCL, other cancers, and the healthy control group. However, Hb/RDW in the CRC group was lower than the other three groups. Moreover, there were significant differences in Hb/RDW and CEA among different T-N-M stages (all P< 0.05). Multivariate logistic regression showed that low level of Hb/RDW and high level of CAR, CEA, PCT were risk factors for CRC, and are correlated with CRC stage. Additionally, the area under the receiver operating characteristic curve (AUC) of Hb/RDW+CEA (AUC: 0.735), CAR+CEA (AUC: 0.748), PCT+CEA (AUC: 0.807) was larger than that of Hb/RDW (AUC: 0.503), CAR (AUC: 0.614), or PCT (AUC: 0.713) alone (all P< 0.001) in distinguishing CRC from BCL. CONCLUSIONS: Hb/RDW, CAR, PCT, and CEA are independent risk factors for CRC. Hb/RDW, CAR, and PCT combined with CEA have significant value for auxiliary differential diagnosis of CRC and BCL.

Effects of wastewater treatment plant effluent on microbial risks of pathogens and their antibiotic resistance in the receiving river.

The increase in effluent discharge from wastewater treatment plants (WWTPs) into urban rivers has raised concerns about the potential effects on pathogen risks. This study utilized metagenomic sequencing combined with flow cytometry to analyze pathogen concentrations and antibiotic resistance in a typical effluent-receiving river. Quantitative microbial risk assessment (QMRA) was employed to assess the microbial risks of pathogens. The results indicated obvious spatial-temporal differences (i.e., summer vs. winter and effluent vs. river) in microbial composition. Microcystis emerged as a crucial species contributing to these variations. Pathogen concentrations were found to be higher in the river than in the effluent, with the winter exhibiting higher concentrations compared to the summer. The effluent discharge slightly increased the pathogen concentrations in the river in summer but dramatically reduced them in winter. The combined effects of cyanobacterial bloom and high temperature were considered key factors suppressing pathogen concentrations in summer. Moreover, the prevalence of antibiotic resistance of pathogens in the river was inferior to that in the effluent, with higher levels in winter than in summer. Three high-concentration pathogens (Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) were selected for QMRA. The results showed that the risks of pathogens exceeded the recommended threshold value. Escherichia coli posed the highest risks. And the fishing scenario posed significantly higher risks than the walking scenario. Importantly, the effluent discharge helped reduce the microbial risks in the receiving river in winter. The study contributes to the management and decision-making regarding microbial risks in the effluent-receiving river.

MRI Radiomics Features of Adenohypophysis Determine the Activation of Hypothalamic-Pituitary-Gonadal Axis in Peri-Puberty Children.

BACKGROUND: The status of the hypothalamic-pituitary-gonadal (HPG) axis is important for assessing the onset of physiological or pathological puberty. The reference standard gonadotropin-releasing hormone (GnRH) stimulation test requires hospital admission and repeated blood samples. A simple noninvasive method would be beneficial. OBJECTIVES: To explore a noninvasive method for evaluating HPG axis activation in children using an MRI radiomics model. STUDY TYPE: Retrospective. POPULATION: Two hundred thirty-nine children (83 male; 3.6-14.6 years) with hypophysial MRI and GnRH stimulation tests, randomly divided a training set (168 children) and a test set (71 children). FIELD STRENGTH/SEQUENCE: 3.0 T, 3D isotropic fast spin echo (CUBE) T1-weighted imaging (T1WI) sequences. ASSESSMENT: Radiomics features were extracted from sagittal 3D CUBE T1WI, and imaging signatures were generated using the least absolute shrinkage and selection operator (LASSO) with 10-fold cross-validation. Diagnostic performance for differential diagnosis of HPG status was compared between a radiomics model and MRI features (adenohypophyseal height [aPH] and volume [aPV]). STATISTICAL TESTS: Receiver operating characteristic (ROC) and decision curve analysis (DCA). A P value <0.05 was considered statistically significant. RESULTS: Eight hundred fifty-one radiomics features were extracted and reduced to 10 by the LASSO method in the training cohort. The radiomics model based on CUBE T1WI showed good performance in assessment of HPG axis activation with an area under the ROC curve (AUC) of 0.81 (95% CI: 0.71, 0.91) in the test set. The AUC of the radiomics model was significantly higher than that of aPH (0.81 vs. 0.65) but there was no significant difference compared to aPV (0.81 vs. 0.78, P = 0.58). In DCA analysis, the radiomics signature showed higher net benefit over the aPV and aPH models. DATA CONCLUSIONS: The MRI radiomics model has potential to assess HPG axis activation status noninvasively, potentially providing valuable information in the diagnosis of patients with pathological puberty onset. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Split aptamer-based sandwich-type ratiometric biosensor for dual-modal photoelectrochemical and electrochemical detection of 17ß-estradiol.

BACKGROUND: As one of the most potent environmental estrogens, 17ß-estradiol (E2), which can be enriched into organisms through the food chain and cause harmful biological effects in humans, has been frequently detected in the water environment of the world. High performance liquid chromatography (HPLC) and gas chromatograohy-mass spectrometry (GC/MS) have been widely used for quantification of E2. Despite excellent accuracy, tedious pretreatment and expensive instruments result in their limited application. It is clear that there is an urgent need to establish simple, sensitive and accurate methods for the determination of E2. RESULTS: A split aptamer-based sandwich-type ratiometric biosensor based on split aptamer was developed by coupling photoelectrochemical and electrochemical assays for E2 detection. For analysis, the two fragments of split aptamer recognized E2 by forming sandwich structure, which triggered hybridization chain reaction (HCR) to produce double-stranded DNA (dsDNA) with CdTe quantum dots (QDs) labeled hairpin DNA. The resultant dsDNA can further absorb methylene blue (MB) to sensitize CdTe QDs for an enlarged photocurrent (IPEC) and output a redox current of IMB, and both of them acted as response signals for detection; [Fe(CN)6]3-/4- probe produced redox current of I[Fe(CN)6]3-/4- as reference signal. Using IMB/I[Fe(CN)6]3-/4- and IPEC/I[Fe(CN)6]3-/4- as yardsticks, the developed split aptamer-based sandwich-type ratiometric biosensor provides two linear ranges of 0.1-5000 pg mL-1 for IMB/I[Fe(CN)6]3-/4- and 0.1-10000 pg mL-1 for IPEC/I[Fe(CN)6]3-/4- with detection limits of 0.06 pg mL-1 and 0.02 pg mL-1, respectively. SIGNIFICANCE: These results of the biosensor are benefiting from the coupling of photoelectrochemical (PEC) and electrochemical (EC) assays as well as the unique cooperative recognition mechanism of split aptamer. This method not only enabled the biosensor to be successfully applied to the determination of E2 in lake water, but also broadens the prospects for the realization of sensitive and accurate detection of E2.

Unexpectedly high levels and health risks of atmospheric polychlorinated biphenyls in modern mechanical dismantling of obsolete electrical equipment: Investigations in a large integrated e-waste dismantling industrial estate.

Large industrial estates for electrical and electronic waste (e-waste) mechanical dismantling and recycling are gradually replacing outmoded small factories and intensive domestic workshops for e-waste manual and chemical dismantling. However, the air pollution and health risks of persistent organic pollutants during the modern mechanical processing of e-waste, especially obsolete electrical equipment, still remain unclear. Here, unexpectedly high levels (409.3 ng/m3) and health risks of airborne polychlorinated biphenyls (PCBs) were found during the mechanical processing of obsolete electric equipment or parts in a large integrated dismantling industrial estate, which is comparable to or a dozen times higher than those reported during chemical processing. In contrast, the levels (936.0 pg/m3) and health risks of particulate polybrominated diphenyl ethers (PBDEs) were all lower than those of previous studies. PCB emissions (44.9-3300.5 ng/m3) varied significantly across six mechanical dismantling places specifically treating waste motors, electrical appliances, hardware, transformers, and metals, respectively. The high PCB content and mass processing number of obsolete electrical equipment probably result in the highest PCB emissions from the mechanical dismantling of obsolete motors, followed by waste electrical appliances and metals. The PCB non-cancer and cancer risks associated with inhalation and dermal exposure in different mechanical dismantling places were all above the given potential risk limits. In particular, the health risks of dismantling obsolete motor exceeded the definite risk levels. Little difference in PCB emissions and health risks between working and non-working time suggested the importance of PCB volatilization from most e-waste. Such high PCB emissions and health risks of PCBs undoubtedly posed a severe threat to frontline workers, but fortunately, they decreased significantly with the increasing distance from the industrial estate. We highlight that PCB emissions and associated health risks from obsolete electrical equipment with high PCB content during mechanical dismantling activities should be of great concern.

A pan-cancer analysis of the MAPK family gene and their association with prognosis, tumor microenvironment, and therapeutic targets.

The mitogen-activated protein kinases family of genes plays a crucial role in a wide range of inflammatory responses in the human body. The MAPK family of genes includes ERK, ERK5, JNK, P-38 mitogen-activated protein kinases. However, the correlation between MAPK family gene expression and pan-cancer prognosis, as well as the tumor microenvironment, has not been extensively studied. This study integrated multiple bioinformatics analysis methods to assess the expression and prognostic value of MAPK family genes, as well as their relationship with tumor microenvironment in patients with pan-cancer. The results showed that ERK, JNK, and P-38 MAPK expression were found to be significantly upregulated in rectum adenocarcinoma (READ), colon adenocarcinoma/rectum adenocarcinoma esophageal carcinoma (COADREAD), and kidney renal clear cell carcinoma (KIRC), and significantly downregulated in acute myeloid leukemia. And the results revealed good prognostic results for ERK, JNK, and P-38 MAPK in READ, COADREAD, and KIRC. We observed significant positive correlation between MAPK family gene expression and immune scores especially dendritic cells in READ, COADREAD, and KIRC. And we observed that the expression levels of MAPK family genes were significantly correlated with the expression of immune-related genes, such as CXCL1, CXCL2, CXCL8, CXCR1, CXCR2, CTLA-4, CD80, CD86, and CD28, suggesting their important role in regulating immune infiltrates and tumor progression. Therefore, our study suggested that MAPK family gene plays an important role in regulating immune infiltrates and tumor progression.

A Combination of CPI-0610 and SAHA Induces Apoptosis through STAT3 and p38 Signalling Pathways in Diffuse Large B-cell Lymphoma Cells.

BACKGROUND: Although immunotherapies have greatly improved diffuse large B-cell lymphoma (DLBCL) prognosis, a proportion of patients remain to be relapsed or refractory. Therefore, the identification of novel therapeutic targets and drugs is urgently required. Inhibition of the bromodomain and extra-terminal (BET) proteins has been a promising therapeutic strategy for various haematologic cancers. CPI-0610 is a potent and selective BET inhibitor. The effects of CPI-0610 in DLBCL cells have not been reported yet. AIMS: The aim of this study was to assess the effects of CPI-0610 in DLBCL and its underlying mechanisms. METHODS: DLBCL cells were treated with CPI-0610, followed by measuring cell viability, cell cycle, apoptosis, autophagy, and specific cell signaling pathways. Moreover, immunodeficient mice were engrafted with SUDHL2 cells and then treated with CPI-0610 for analysis of tumor burden. We also analyzed the synergistic effect of CPI-0610 with histone deacetylase inhibitor suberoylanilide hydroxamic acid. RESULTS: The present study demonstrated that CPI-0610 displayed cell cytotoxicity by arresting the G1 cell cycle and inducing endogenous and exogenous apoptotic pathways. Additionally, CPI-0610 decreased BRD4 and c-Myc expressions and affected MAPK, JAK/STAT, and AKT signalling pathways in human DLBCL cells. An in vivo experiment exhibited that CPI-0610 decreased the primary tumour growth of the DLBCL xenograft model. Furthermore, the use of CPI-0610 in combination with suberoylanilide hydroxamic acid exhibited a specific synergistic effect in inducing apoptosis through the regulation of STAT3 and p38. CONCLUSION: Targeting BET may be an effective therapeutic strategy and potentiated by a combination with histone deacetylase inhibition in DLBCL.

Severe anemia, severe leukopenia, and severe thrombocytopenia of amphotericin B deoxycholate-based induction therapy in patients with HIV-associated talaromycosis: a subgroup analysis of a prospective multicenter cohort study.

BACKGROUND: This study's objective was to investigate the predictors for severe anemia, severe leukopenia, and severe thrombocytopenia when amphotericin B deoxycholate-based induction therapy is used in HIV-infected patients with talaromycosis. METHODS: A total of 170 HIV-infected patients with talaromycosis were enrolled from January 1st, 2019, to September 30th, 2020. RESULTS: Approximately 42.9%, 20.6%, and 10.6% of the enrolled patients developed severe anemia, severe leukopenia, and severe thrombocytopenia, respectively. Baseline hemoglobin level < 100 g/L (OR = 5.846, 95% CI: 2.765 ~ 12.363), serum creatinine level > 73.4 µmol/L (OR = 2.573, 95% CI: 1.157 ~ 5.723), AST/ALT ratio > 1.6 (OR = 2.479, 95% CI: 1.167 ~ 5.266), sodium level ≤ 136 mmol/liter (OR = 4.342, 95% CI: 1.747 ~ 10.789), and a dose of amphotericin B deoxycholate > 0.58 mg/kg/d (OR = 2.504, 95% CI:1.066 ~ 5.882) were observed to be independent risk factors associated with the development of severe anemia. Co-infection with tuberculosis (OR = 3.307, 95% CI: 1.050 ~ 10.420), and platelet level (per 10 × 109 /L) (OR = 0.952, 95% CI: 0.911 ~ 0.996) were shown to be independent risk factors associated with the development of severe leukopenia. Platelet level < 100 × 109 /L (OR = 2.935, 95% CI: 1.075 ~ 8.016) was identified as the independent risk factor associated with the development of severe thrombocytopenia. There was no difference in progression to severe anemia, severe leukopenia, and severe thrombocytopenia between the patients with or without fungal clearance at 2 weeks. 10 mg on the first day of amphotericin B deoxycholate was calculated to be independent risk factors associated with the development of severe anemia (OR = 2.621, 95% CI: 1.107 ~ 6.206). The group receiving a starting amphotericin B dose (10 mg, 20 mg, daily) exhibited the highest fungal clearance rate at 96.3%, which was significantly better than the group receiving a starting amphotericin B dose (5 mg, 10 mg, 20 mg, daily) (60.9%) and the group receiving a starting amphotericin B dose (5 mg, 15 mg, and 25 mg, daily) (62.9%). CONCLUSION: The preceding findings reveal risk factors for severe anemia, severe leukopenia, and severe thrombocytopenia. After treatment with Amphotericin B, these severe adverse events are likely unrelated to fungal clearance at 2 weeks. Starting amphotericin B deoxycholate at a dose of 10 mg on the first day may increase the risk of severe anemia but can lead to earlier fungal clearance. TRIAL REGISTRATION: ChiCTR1900021195. Registered 1 February 2019.

Polarity-Sensitive Probe for Two-Photon Fluorescence Lifetime Imaging of Lipid Droplets In Vitro and In Vivo.

Lipid droplets (LDs) are crucial organelles used to store lipids and participate in lipid metabolism in cells. The abnormal aggregation and polarity change of LDs are associated with the occurrence of diseases, such as steatosis. Herein, the polarity-sensitive probe TBPCPP with a donor-acceptor-π-acceptor (D-A-π-A) structure was designed and synthesized. The TBPCPP has a large Stokes shift (∼220 nm), excellent photostability, high LD targeting, and considerable two-photon absorption (TPA) cross-section (∼226 GM), enabling deep two-photon imaging (∼360 µm). In addition, the fluorescence lifetime of TBPCPP decreases linearly with increasing solvent polarity. Therefore, with the assistance of two-photon fluorescence lifetime imaging microscopy (TP-FLIM), TBPCPP has successfully achieved not only the visualization of polarity changes caused by LD accumulation in HepG-2 cells but also lipid-specific imaging and visualization of different polarities in lipid-rich regions in zebrafish for the first time. Furthermore, TP-FLIM revealed that the polarity gradually decreases during steatosis in HepG-2 cells, which provided new insights into the diagnosis of steatosis.

Impaired topological properties of cortical morphological brain networks correlate with motor symptoms in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterized by loss of selectively vulnerable neurons within the basal ganglia circuit and progressive atrophy in subcortical and cortical regions. However, the impact of neurodegenerative pathology on the topological organization of cortical morphological networks has not been explored. The aims of this study were to investigate altered network patterns of covariance in cortical thickness and complexity, and to evaluate how morphological network integrity in PD is related to motor impairment. METHODS: Individual morphological networks were constructed for 50 PD patients and 46 healthy controls (HCs) by estimating interregional similarity distributions in surface-based indices. We performed graph theoretical analysis and network-based statistics to detect PD-related alterations and further examined the correlation of network metrics with clinical scores. Furthermore, support vector regression based on topological characteristics was applied to predict the severity of motor impairment in PD. RESULTS: Compared with HCs, PD patients showed lower local efficiency (p = 0.004), normalized characteristic path length (p = 0.022), and clustering coefficient (p = 0.005) for gyrification index-based morphological brain networks. Nodal topological abnormalities were mainly in the frontal, parietal and temporal regions, and impaired morphological connectivity was involved in the sensorimotor and default mode networks. The support vector regression model using network-based features allowed prediction of motor symptom severity with a correlation coefficient of 0.606. CONCLUSIONS: This study identified a disrupted topological organization of cortical morphological networks that could substantially advance our understanding of the network degeneration mechanism of PD and might offer indicators for monitoring disease progression.

Which qualities should built environment possess to ensure satisfaction of higher-education students with remote education during pandemics?

The built environment may be considered a complex system comprising several parts (including people, organizations, and physical structures). Since the emergence of the COVID-19 virus in recent years, there has been an explosion in the usage of mobile learning applications for classroom instruction. Research on the diffusion of mobile learning is lacking. This study examines the perceptions and experiences of many aspects of online education from the viewpoint of Chinese HEIs and university students who shifted to online modes of instruction during the COVID-19 outbreak. This research aimed to determine whether or not college students were happy with the resources available to them, how their teachers communicated with them, how they were evaluated, and the conditions in which they studied at home. It also looked at the pros and cons of online learning from the students' points of view. For this study, researchers opted for a cross-sectional survey using an online questionnaire. Information was gathered from 450 students from different Chinese tertiary institutions. To this end, we reflect on the experiences and perspectives of postgraduate students in urban design and discuss the results of an online survey conducted during the 2021-2022 academic year's subject delivery period, which included activities such as assessment, feedback, field study visits, workshops, and the use of digital platforms. PLS-SEM, which stands for partial least square structural equation modeling, is used in order to evaluate the proposed model. Therefore, the findings show that the research model offered for this investigation could explain the diversity in the actual use of mobile learning systems. This would provide helpful insight into the effect of educational, environmental, and quality factors on the actual use of remote education systems. It was shown that quality concerns acted as a mediator between institutional policy, change management, and the implementation of mobile learning systems in actual classrooms. The findings also indicate that the level of pleasure students feel acts as a moderating factor between the degree to which the mobile learning system is used and its overall level of quality. According to the findings of these studies, academic institutions may enhance their use of mobile learning applications and get more benefits from these systems if they adhere to the suggestions stated in these studies.

Multisite rTMS combined with cognitive training modulates effective connectivity in patients with Alzheimer's disease.

Purpose: To investigate the effective connectivity (EC) changes after multisite repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (COG). Method: We selected 51 patients with mild or moderate Alzheimer's disease (AD) and delivered 10 Hz rTMS over the left dorsal lateral prefrontal cortex (DLPFC) and the lateral temporal lobe (LTL) combined with COG or sham stimulation for 4 weeks. The selected AD patients were divided into real (real rTMS+COG, n = 11) or sham (sham rTMS+COG, n = 8) groups to undergo neuropsychological assessment, resting-state fMRI, and 3D brain structural imaging before (T0), immediately at the end of treatment (T4), and 4 weeks after treatment (T8). A 2 × 3 factorial design with "time" as the within-subjects factor (three levels: T0, T4, and T8) and "group" as the between-subjects factor (two levels: real and sham) was used to investigate the EC changes related to the stimulation targets in the rest of the brain, as well as the causal interactions among seven resting-state networks based on Granger causality analysis (GCA). Results: At the voxel level, the EC changes from the left DLPFC out to the left inferior parietal lobe and the left superior frontal gyrus, as well as from the left LTL out to the left orbital frontal cortex, had a significant group × time interaction effect. At the network level, a significant interaction effect was identified in the increase in EC from the limbic network out to the default mode network. The decrease in EC at the voxel level and the increase in EC at the network level were both associated with the improved ability to perform activities of daily living and cognitive function. Conclusion: Multisite rTMS combined with cognitive training can modulate effective connectivity in patients with AD, resulting in improved ability to perform activities of daily living and cognitive function.