Genetically Engineered Membrane-Coated Nanoparticles for Enhanced Prostate-Specific Membrane Antigen Targeting and Ferroptosis Treatment of Castration-Resistant Prostate Cancer.

Conventional androgen deprivation therapy (ADT) targets the androgen receptor (AR) inhibiting prostate cancer (PCa) progression; however, it can eventually lead to recurrence as castration-resistant PCa (CRPC), which has high mortality rates and lacks effective treatment modalities. The study confirms the presence of high glutathione peroxidase 4 (GPX4) expression, a key regulator of ferroptosis (i.e., iron-dependent program cell death) in CRPC cells. Therefore, inducing ferroptosis in CRPC cells might be an effective therapeutic modality for CRPC. However, nonspecific uptake of ferroptosis inducers can result in undesirable cytotoxicity in major organs. Thus, to precisely induce ferroptosis in CRPC cells, a genetic engineering strategy is proposed to embed a prostate-specific membrane antigen (PSMA)-targeting antibody fragment (gy1) in the macrophage membrane, which is then coated onto mesoporous polydopamine (MPDA) nanoparticles to produce a biomimetic nanoplatform. The results indicate that the membrane-coated nanoparticles (MNPs) exhibit high specificity and affinity toward CRPC cells. On further encapsulation with the ferroptosis inducers RSL3 and iron ions, MPDA/Fe/RSL3@M-gy1 demonstrates superior synergistic effects in highly targeted ferroptosis therapy eliciting significant therapeutic efficacy against CRPC tumor growth and bone metastasis without increased cytotoxicity. In conclusion, a new therapeutic strategy is reported for the PSMA-specific, CRPC-targeting platform for ferroptosis induction with increased efficacy and safety.

Effectiveness of Hydromorphone Hydrochloride Combined with Bupivacaine for Combined Spinal and Epidural Anaesthesia in Reducing Postpartum Urinary Retention: A Retrospective Study.

BACKGROUND: Postpartum urinary retention is a common complication following caesarean section, with significant implications for patient comfort and recovery. Combined spinal and epidural anaesthesia is frequently employed for caesarean section, but postpartum urinary retention remains a clinical concern despite its benefits. This study aimed to investigate the effectiveness of hydromorphone hydrochloride combined with bupivacaine for combined spinal and epidural anaesthesia in reducing postpartum urinary retention. METHODS: A retrospective analysis was conducted on patients who received combined spinal and epidural anaesthesia for caesarean section. The control group received bupivacaine, whereas the hydromorphone hydrochloride combined with bupivacaine spinal-epidural anaesthesia (HB) group received hydromorphone hydrochloride combined with bupivacaine. Data on demographics, anaesthesia, operative characteristics, postoperative urinary retention and adverse events were collected and analysed. RESULTS: The study enrolled 105 patients, with a control group (n = 51) receiving bupivacaine spinal-epidural anaesthesia and an observation group (n = 54) receiving hydromorphone hydrochloride combined with bupivacaine spinal-epidural anaesthesia. The incidence of postoperative urinary retention was significantly lower in the HB group than in the control group (3.70% vs. 17.65%, p = 0.044). Furthermore, the HB group exhibited a shorter time to first voiding after anaesthesia (5.72 ± 1.26 h vs. 6.28 ± 1.35 h, p = 0.029), lower peak postvoid residual volume (168.57 ± 25.09 mL vs. 180.43 ± 30.21 mL, p = 0.032), decreased need for postoperative catheterisation (5.56% vs. 21.57%, p = 0.034) and shorter duration of urinary catheterisation (10.92 ± 2.61 h vs. 12.04 ± 2.87 h, p = 0.039) than the control group. Correlation analysis supported a negative correlation between hydromorphone supplementation and parameters related to postoperative urinary retention. Multivariate regression analysis demonstrated a significant association between the duration of urinary catheterisation and the use of hydromorphone with the occurrence of postoperative urinary retention, providing further insights into the multifactorial nature of this postoperative complication. CONCLUSIONS: The addition of hydromorphone hydrochloride to bupivacaine for combined spinal and epidural anaesthesia was associated with a reduced incidence of postpartum urinary retention and improved postoperative voiding parameters, without significantly increasing the risk of adverse events.

Synthesis towards Phainanoid F: Photo-induced 6π-Electrocyclization for Constructing Contiguous All-Carbon Quaternary Centers.

In this paper, we report an efficient strategy for synthesizing the DEFGH rings of phainanoid F. The key to the construction of the 13,30-cyclodammarane skeleton of the molecule was a photo-induced 6π-electrocyclization and a homoallylic elimination. Notably, this is a rare example of using electrocyclization reaction to simultaneously construct two vicinal quaternary carbons in total synthesis. The strategy outlined here forms the basis of our total synthesis of Phainanoid F, and it could also serve as a generally applicable approach for synthesizing other natural products containing similar 13,30-cyclodammarane skeletons.

[IgG78-DM1 inhibits pulmonary fibrosis by targeting and killing CD248-positive myofibroblasts in mice].

Objective To investigate the therapeutic effect of targeting and killing CD248-positive myofibroblasts on bleomycin-induced pulmonary fibrosis in mice. Methods IgG78-DM1, an antibody-maytansine 1 (DM1) conjugate targeting CD248, was prepared. The drug conjugation efficiency was measured and calculated by UV spectrophotometer, and the identification of IgG78-DM1 was performed through SDS-PAGE and Western blot analysis. In vitro, the binding activity of IgG78-DM1 on CD248-positive myofibroblasts was detected by flow cytometry and the cytotoxicity of IgG78-DM1 to CD248-positive myofibroblasts was evaluated by CCK-8 assay. In vivo, C57BL/6 male mice were randomly divided into control group, idiopathic pulmonary fibrosis group, human IgG-DM1 (hIgG-DM1) control group, and IgG78-DM1 treatment group. Then, the mouse models with pulmonary fibrosis induced by bleomycin were constructed. Two weeks later, the animal models were intravenously injected with IgG78-DM1. After the treatment of two weeks, lung tissues were collected for Masson staining and Sirius Red staining to evaluate the degree of pulmonary fibrosis. Real-time fluorescence quantitative PCR was used to measure the expression levels of CD248, as well as markers of fibroblastic activation including alpha-smooth muscle actin (α-SMA) and type I collagen alpha 1 (COL1A1). The safety of IgG78-DM1 was preliminarily assessed by conducting liver and kidney function tests. Results IgG78-DM1 was successfully prepared, and its drug conjugation ratio was 3.2. The antibody structure remained stable after conjugation, allowing effective binding and cytotoxicity against CD248-positive myofibroblasts. After treatment with IgG78-DM1, the degree of pulmonary fibrosis in mice significantly reduced, accompanied by the decrease of the expression of CD248, α-SMA, and COL1A1. The liver and kidney function of the mice remained at normal levels compared to the normal control group. Conclusion IgG78-DM1 effectively inhibits pulmonary fibrosis in mice by targeting and killing CD248-positive myofibroblasts. The safety of this strategy is preliminarily assessed.

Oral treatment with 10% potassium iodide solution for refractory cutaneous-disseminated sporotrichosis in an immunocompetent adult: Case report.

Sporotrichosis has multiple clinical manifestations, and its cutaneous-disseminated form is uncommon and, in most cases, related to immunosuppressive conditions. We report the case of a 47-year-old male patient who presented with multiple cutaneous nodules and ulcers on the left upper limb and the right thigh, with no other comorbidities. Until the diagnosis was confirmed, the patient was initially given empiric antifungal treatment with itraconazole, which showed unsatisfactory results at a local hospital. Then, he was treated with voriconazole, which led to the slow improvement of his skin lesions. At one point during the voriconazole treatment course, the patient briefly self-discontinued voriconazole for economic reasons, and the lesions recurred and worsened. The patient was finally diagnosed with cutaneous-disseminated sporotrichosis based on the isolation and identification of Sporothrix globosa. Susceptibility testing revealed that the isolate was resistant to itraconazole, fluconazole, voriconazole, terbinafine, and amphotericin. Considering the patient's poor financial condition, potassium iodide was administered. After 1-month of therapy with potassium iodide, he reported rapid improvement of his skin lesions. The patient continued potassium iodide treatment for another 5 months until the full resolution of lesions was achieved.

Nanofiber self-consistent additive manufacturing process for 3D microfluidics.

3D microfluidic devices have emerged as powerful platforms for analytical chemistry, biomedical sensors, and microscale fluid manipulation. 3D printing technology, owing to its structural fabrication flexibility, has drawn extensive attention in the field of 3D microfluidics fabrication. However, the collapse of suspended structures and residues of sacrificial materials greatly restrict the application of this technology, especially for extremely narrow channel fabrication. In this paper, a 3D printing strategy named nanofiber self-consistent additive manufacturing (NSCAM) is proposed for integrated 3D microfluidic chip fabrication with porous nanofibers as supporting structures, which avoids the sacrificial layer release process. In the NSCAM process, electrospinning and electrohydrodynamic jet (E-jet) writing are alternately employed. The porous polyimide nanofiber mats formed by electrospinning are ingeniously applied as both supporting structures for the suspended layer and percolating media for liquid flow, while the polydimethylsiloxane E-jet writing ink printed on the nanofiber mats (named construction fluid in this paper) controllably permeates through the porous mats. After curing, the resultant construction fluid-nanofiber composites are formed as 3D channel walls. As a proof of concept, a microfluidic pressure-gain valve, which contains typical features of narrow channels and movable membranes, was fabricated, and the printed valve was totally closed under a control pressure of 45 kPa with a fast dynamic response of 52.6 ms, indicating the feasibility of NSCAM. Therefore, we believe NSCAM is a promising technique for manufacturing microdevices that include movable membrane cavities, pillar cavities, and porous scaffolds, showing broad applications in 3D microfluidics, soft robot drivers or sensors, and organ-on-a-chip systems.

Incorporation and improvement of a heterogeneous chemistry mechanism in the atmospheric chemistry model GRAPES_Meso5.1/CUACE and its impacts on secondary inorganic aerosol and PM2.5 simulations in Middle-Eastern China.

Heterogeneous chemistry is considered one of the critical pathways of secondary inorganic aerosol (SIA) productions. In this study, a heterogeneous chemistry mechanism is incorporated into the atmospheric chemistry model GRAPES_Meso5.1/CUACE. Varying uptake coefficient schemes of SO2 and NO2 are compared and the equivalent ratio of inorganic aerosol (ER)-dependent scheme for SO2 and relative humidity (RH)/ER-dependent scheme for NO2 are used to form the improved heterogeneous chemistry. Focusing on a severe haze episode in Middle-Eastern China, the impacts of heterogeneous mechanism on SIA and PM2.5 composition are investigated based on the updated model. Study results show that the differences in RH or ER uptake coefficients result in obvious differences in sulfate and nitrate concentrations, especially during the severe pollution period, because the ER schemes restrict the excessive production of sulfate and nitrate under high RH effectively by including the self-limitation of heterogeneous reactions, which shows better performance in capturing the magnitude and temporal variations of surface SIA and PM2.5. Normalized mean bias of sulfate, nitrate, ammonium, and PM2.5 in megacity Beijing decreases from -27.0, -28.3, -58.2, and -26.3 to 1.0, -2.2, -47.2, and -16.5 %, respectively. And the fractions of sulfate, nitrate, ammonium, and organics during the polluted period change from 13.7, 19.3, 6.9, and 60.1 to 16.5, 23.0, 7.6, and 52.9 %, respectively, which is more consistent with the observation (16.0, 23.2, 14.1, and 46.7 %). SIA and PM2.5 simulations in another megacity Shanghai have the similar improvements. The modeled SIA by heterogeneous processes contributes 11.7 % of total PM2.5 in Beijing and 22.5 % in Shanghai. That is 13.5 % in the Chinese megalopolis Beijing-Tianjin-Hebei and 19.8 % in Yangtze-River-Delta, indicating a considerable contribution of heterogeneous pathways to haze pollution. This work indicates the importance of detailed and reasonable heterogeneous schemes for better SIA and haze/fog prediction in the atmospheric chemistry model.

A role for the mitotic proteins Bub3 and BuGZ in transcriptional regulation of catalase-3 expression.

The spindle assembly checkpoint factors Bub3 and BuGZ play critical roles in mitotic process, but little is known about their roles in other cellular processes in eukaryotes. In aerobic organisms, transcriptional regulation of catalase genes in response to developmental or environmental stimuli is necessary for redox homeostasis. Here, we demonstrate that Bub3 and BuGZ negatively regulate cat-3 transcription in the model filamentous fungus Neurospora crassa. The absence of Bub3 caused a significant decrease in BuGZ protein levels. Our data indicate that BuGZ and Bub3 interact directly via the GLEBS domain of BuGZ. Despite loss of the interaction, the amount of BuGZ mutant protein negatively correlated with the cat-3 expression level, indicating that BuGZ amount rather than Bub3-BuGZ interaction determines cat-3 transcription level. Further experiments demonstrated that BuGZ binds directly to the cat-3 gene and responses to cat-3 overexpression induced by oxidative stresses. However, the zinc finger domains of BuGZ have no effects on DNA binding, although mutations of these highly conserved domains lead to loss of cat-3 repression. The deposition of BuGZ along cat-3 chromatin hindered the recruitment of transcription activators GCN4/CPC1 and NC2 complex, thereby preventing the assembly of the transcriptional machinery. Taken together, our results establish a mechanism for how mitotic proteins Bub3 and BuGZ functions in transcriptional regulation in a eukaryotic organism.

Development and application of an automated air quality forecasting system based on machine learning.

As one of the most concerned issues in modern society, air quality has received extensive attentions from the public and the government, which promotes the continuous development and progress of air quality forecasting technology. In this study, an automated air quality forecasting system based on machine learning has been developed and applied for daily forecasts of six common pollutants (PM2.5, PM10, SO2, NO2, O3, and CO) and pollution levels, which can automatically find the best "Model + Hyperparameters" without human intervention. Five machine learning models and an ensemble model (Stacked Generalization) were integrated into the system, supported by a knowledge base containing the meteorological observed data, pollutant concentrations, pollutant emissions, and model reanalysis data. Then five-year data (2015-2019) of Beijing, Shanghai, Guangzhou, Chengdu, Xi'an, Wuhan, and Changchun in China, were used as an application case to study the effectiveness of the automated forecasting system. Based on the analysis of seven evaluation criteria and pollution level forecasts, combined with the forecasting results for the next 3-days, it is found that the automated system can achieve satisfactory forecasting performance, better than most of numerical model results. This implied that the developed system unveils a good application prospect in the field of environmental meteorology.

A new parameterization of uptake coefficients for heterogeneous reactions on multi-component atmospheric aerosols.

Based on laboratory studies and field observations, a new parameterization of uptake coefficients for heterogeneous reactions on multi-component aerosols is developed in this work. The equivalent ratio (ER) of inorganic aerosol is used to establish the quantitative relationship between the heterogeneous uptake coefficients and the composition of aerosols. Incorporating the new ER-dependent scheme, the WRF-CUACE model has been applied to simulate sulfate mass concentrations during December 2017 in the Beijing-Tianjin-Hebei region and evaluate the role of aerosol chemical components played in the sulfate formation. Simulated temporal variations and magnitudes of sulfate show good agreement with the observations by using this new scheme. From clean to polluted cases, although both dominant cations and anions increase significantly, the equivalent ratio decreases gradually and is closer to unity, representing the variation of aerosol compositions, which inhibits the heterogeneous uptake of SO2, with the uptake coefficient decreasing from 1 × 10-4 to 5.3 × 10-5. Based on this phenomenon, a self-limitation process for heterogeneous reactions with the increasing secondary inorganic aerosol from clean to polluted cases is proposed.

The Neurospora RNA polymerase II kinase CTK negatively regulates catalase expression in a chromatin context-dependent manner.

Clearance and adaptation to reactive oxygen species (ROS) are crucial for cell survival. As in other eukaryotes, the Neurospora catalases are the main enzymes responsible for ROS clearance and their expression are tightly regulated by the growth and environmental conditions. The RNA polymerase II carboxyl terminal domain (RNAPII CTD) kinase complex (CTK complex) is known as a positive elongation factor for many inducible genes by releasing paused RNAPII near the transcription start site and promoting transcription elongation. However, here we show that deletion of CTK complex components in Neurospora led to high CAT-3 expression level and resistance to H2 O2 -induced ROS stress. The catalytic activity of CTK-1 is required for such a response. On the other hand, CTK-1 overexpression led to decreased expression of CAT-3. ChIP assays shows that CTK-1 phosphorylates the RNAPII CTD at Ser2 residues in the cat-3 ORF region during transcription elongation and deletion of CTK-1 led to dramatic decreases of SET-2 recruitment and H3K36me3 modification. As a result, histones at the cat-3 locus become hyperacetylated to promote its transcription. Together, these results demonstrate that the CTK complex is negative regulator of cat-3 expression by affecting its chromatin structure.

Increasing the Unneddylated Cullin1 Portion Rescues the csn Phenotypes by Stabilizing Adaptor Modules To Drive SCF Assembly.

The dynamic SCF (Skp1-cullin1-F-box protein) assembly is controlled by cycles of cullin neddylation/deneddylation based on the deneddylation activity of the COP9 signalosome (CSN) and global sequestration of cullins by CAND1. However, acceptance of this prediction was hampered by the results of recent studies, and the regulatory mechanism and key players remain to be identified. We found that maintaining a proper Cul1Nedd8/Cul1 ratio is crucial to ensure SCF functions. Reducing the high Cul1Nedd8/Cul1 ratios in csn mutants through ectopic expression of the nonneddylatable Cul1K722R proteins or introducing the endogenous cul1K722R point mutation significantly rescues their defective phenotypes. In vivo protein degradation assays revealed that the large portion of the unneddylated Cul1 contributes to F-box protein stabilization. Moreover, the unneddylated Cul1 tends to associate with adaptor modules, and disruption of Cul1-Skp-1 binding fails to restore the csn phenotypes. Taking the data together, we propose that unneddylated Cul1 is another central player involved in maintenance of the adaptor module pool through the formation of Cul1-Skp-1-F-box complexes and promotion of rapid SCF assembly.

A 20-year simulated climatology of global dust aerosol deposition.

Based on a 20-year (1991-2010) simulation of dust aerosol deposition with the global climate model CAM5.1 (Community Atmosphere Model, version 5.1), the spatial and temporal variations of dust aerosol deposition were analyzed using climate statistical methods. The results indicated that the annual amount of global dust aerosol deposition was approximately 1161±31Mt, with a decreasing trend, and its interannual variation range of 2.70% over 1991-2010. The 20-year average ratio of global dust dry to wet depositions was 1.12, with interannual variation of 2.24%, showing the quantity of dry deposition of dust aerosol was greater than dust wet deposition. High dry deposition was centered over continental deserts and surrounding regions, while wet deposition was a dominant deposition process over the North Atlantic, North Pacific and northern Indian Ocean. Furthermore, both dry and wet deposition presented a zonal distribution. To examine the regional changes of dust aerosol deposition on land and sea areas, we chose the North Atlantic, Eurasia, northern Indian Ocean, North Pacific and Australia to analyze the interannual and seasonal variations of dust deposition and dry-to-wet deposition ratio. The deposition amounts of each region showed interannual fluctuations with the largest variation range at around 26.96% in the northern Indian Ocean area, followed by the North Pacific (16.47%), Australia (9.76%), North Atlantic (9.43%) and Eurasia (6.03%). The northern Indian Ocean also had the greatest amplitude of interannual variation in dry-to-wet deposition ratio, at 22.41%, followed by the North Atlantic (9.69%), Australia (6.82%), North Pacific (6.31%) and Eurasia (4.36%). Dust aerosol presented a seasonal cycle, with typically strong deposition in spring and summer and weak deposition in autumn and winter. The dust deposition over the northern Indian Ocean exhibited the greatest seasonal change range at about 118.00%, while the North Atlantic showed the lowest seasonal change at around 30.23%. The northern Indian Ocean had the greatest seasonal variation range of dry-to-wet deposition ratio, at around 74.57%, while Eurasia had the lowest, at around 12.14%.