Lysosomal cyst(e)ine storage potentiates tolerance to oxidative stress in cancer cells.

Cyst(e)ine is a key precursor for the synthesis of glutathione (GSH), which protects cancer cells from oxidative stress. Cyst(e)ine is stored in lysosomes, but its role in redox regulation is unclear. Here, we show that breast cancer cells upregulate major facilitator superfamily domain containing 12 (MFSD12) to increase lysosomal cyst(e)ine storage, which is released by cystinosin (CTNS) to maintain GSH levels and buffer oxidative stress. We find that mTORC1 regulates MFSD12 by directly phosphorylating residue T254, while mTORC1 inhibition enhances lysosome acidification that activates CTNS. This switch modulates lysosomal cyst(e)ine levels in response to oxidative stress, fine-tuning redox homeostasis to enhance cell fitness. MFSD12-T254A mutant inhibits MFSD12 function and suppresses tumor progression. Moreover, MFSD12 overexpression correlates with poor neoadjuvant chemotherapy response and prognosis in breast cancer patients. Our findings reveal the critical role of lysosomal cyst(e)ine storage in adaptive redox homeostasis and suggest that MFSD12 is a potential therapeutic target.

A Rapid One-Pot Workflow for Sensitive Microscale Phosphoproteomics.

Compared to advancements in single-cell proteomics, phosphoproteomics sensitivity has lagged behind due to low abundance, complex sample preparation, and substantial sample input requirements. We present a simple and rapid one-pot phosphoproteomics workflow (SOP-Phos) integrated with data-independent acquisition mass spectrometry (DIA-MS) for microscale phosphoproteomic analysis. SOP-Phos adapts sodium deoxycholate based one-step lysis, reduction/alkylation, direct trypsinization, and phosphopeptide enrichment by TiO2 beads in a single-tube format. By reducing surface adsorptive losses via utilizing n-dodecyl ß-d-maltoside precoated tubes and shortening the digestion time, SOP-Phos is completed within 3-4 h with a 1.4-fold higher identification coverage. SOP-Phos coupled with DIA demonstrated >90% specificity, enhanced sensitivity, lower missing values (<1%), and improved reproducibility (8%-10% CV). With a sample size-comparable spectral library, SOP-Phos-DIA identified 33,787 ± 670 to 22,070 ± 861 phosphopeptides from 5 to 0.5 µg cell lysate and 30,433 ± 284 to 6,548 ± 21 phosphopeptides from 50,000 to 2,500 cells. Such sensitivity enabled mapping key lung cancer signaling sites, such as EGFR autophosphorylation sites Y1197/Y1172 and drug targets. The feasibility of SOP-Phos-DIA was demonstrated on EGFR-TKI sensitive and resistant cells, revealing the interplay of multipathway Hippo-EGFR-ERBB signaling cascades underlying the mechanistic insight into EGFR-TKI resistance. Overall, SOP-Phos-DIA is an efficient and robust protocol that can be easily adapted in the community for microscale phosphoproteomic analysis.

Magnetoresistance properties in nickel-catalyzed, air-stable, uniform, and transfer-free graphene.

A transfer-free graphene with high magnetoresistance (MR) and air stability has been synthesized using nickel-catalyzed atmospheric pressure chemical vapor deposition. The Raman spectrum and Raman mapping reveal the monolayer structure of the transfer-free graphene, which has low defect density, high uniformity, and high coverage (>90%). The temperature-dependent (from 5 to 300 K) current-voltage (I-V) and resistance measurements are performed, showing the semiconductor properties of the transfer-free graphene. Moreover, the MR of the transfer-free graphene has been measured over a wide temperature range (5-300 K) under a magnetic field of 0 to 1 T. As a result of the Lorentz force dominating above 30 K, the transfer-free graphene exhibits positive MR values, reaching ∼8.7% at 300 K under a magnetic field (1 Tesla). On the other hand, MR values are negative below 30 K due to the predominance of the weak localization effect. Furthermore, the temperature-dependent MR values of transfer-free graphene are almost identical with and without a vacuum annealing process, indicating that there are low density of defects and impurities after graphene fabrication processes so as to apply in air-stable sensor applications. This study opens avenues to develop 2D nanomaterial-based sensors for commercial applications in future devices.

Mercury Immobilization without Methylation in Sulfidogenic Systems Dominated by Sulfur Disproportionating Bacteria.

The sulfidogenic process mediated by sulfate-reducing bacteria (SRB) is not ideal for treating mercury (Hg)-bearing wastewater due to the risk of methylmercury (MeHg) production. Addressing this challenge, our study demonstrated that, under S0-rich conditions and without organic additives, sulfidogenic communities dominated by sulfur-disproportionating bacteria (SDB) can effectively remove Hg(II) and prevent MeHg production. Using various inocula, we successfully established biological sulfidogenic systems driven separately by SDB and SRB. Batch experiments revealed that SDB cultures completely removed Hg(II) from the solution as HgS. Remarkably, no MeHg production was observed in the SDB cultures, while an average concentration of 0.32 µg/L of MeHg was detected in the SRB cultures. The absence of MeHg production in the SDB cultures could be mainly attributed to the cultivation conditions that reshaped the microbial community, resulting in a rapid decline of SRB-dominated Hg-methylating microorganisms. Consequently, the average abundance of the hgcA gene was 28 times lower than the levels before cultivation. Additionally, we found that the enriched Dissulfurimicrobium sp. bin121 can produce biogenic sulfide through sulfur disproportionation but lacks the hgcA gene, rendering it incapable of methylating Hg. Overall, we propose a novel biotechnology driven by SDB that can safely and sustainably treat Hg-bearing wastewater.

Dynamic functional network connectivity in children with profound bilateral congenital sensorineural hearing loss.

BACKGROUND: Functional magnetic resonance imaging (fMRI) studies have revealed extensive functional reorganization in patients with sensorineural hearing loss (SNHL). However, almost no study focuses on the dynamic functional connectivity after hearing loss. OBJECTIVE: This study aimed to investigate dynamic functional connectivity changes in children with profound bilateral congenital SNHL under the age of 3 years. MATERIALS AND METHODS: Thirty-two children with profound bilateral congenital SNHL and 24 children with normal hearing were recruited for the present study. Independent component analysis identified 18 independent components composing five resting-state networks. A sliding window approach was used to acquire dynamic functional matrices. Three states were identified using the k-means algorithm. Then, the differences in temporal properties and the variance of network efficiency between groups were compared. RESULTS: The children with SNHL showed longer mean dwell time and decreased functional connectivity between the auditory network and sensorimotor network in state 3 (P < 0.05), which was characterized by relatively stronger functional connectivity between high-order resting-state networks and motion and perception networks. There was no difference in the variance of network efficiency. CONCLUSIONS: These results indicated the functional reorganization due to hearing loss. This study also provided new perspectives for understanding the state-dependent connectivity patterns in children with SNHL.

Functional connectome automatically differentiates multiple system atrophy (parkinsonian type) from idiopathic Parkinson's disease at early stages.

Differentiating the parkinsonian variant of multiple system atrophy (MSA-P) from idiopathic Parkinson's disease (IPD) is challenging, especially in the early stages. This study aimed to investigate differences and similarities in the brain functional connectomes of IPD and MSA-P patients and use machine learning methods to explore the diagnostic utility of these features. Resting-state fMRI data were acquired from 88 healthy controls, 76 MSA-P patients, and 53 IPD patients using a 3.0 T scanner. The whole-brain functional connectome was constructed by thresholding the Pearson correlation matrices of 116 regions, and topological properties were evaluated through graph theory approaches. Connectome measurements were used as features in machine learning models (random forest [RF]/logistic regression [LR]/support vector machine) to distinguish IPD and MSA-P patients. Regarding graph metrics, early IPD and MSA-P patients shared network topological properties. Both patient groups showed functional connectivity disruptions within the cerebellum-basal ganglia-cortical network, but these disconnections were mainly in the cortico-thalamo-cerebellar circuits in MSA-P patients and the basal ganglia-thalamo-cortical circuits in IPD patients. Among the connectome parameters, t tests combined with the RF method identified 15 features, from which the LR classifier achieved the best diagnostic performance on the validation set (accuracy = 92.31%, sensitivity = 90.91%, specificity = 93.33%, area under the receiver operating characteristic curve = 0.89). MSA-P and IPD patients show similar whole-brain network topological alterations. MSA-P primarily affects cerebellar nodes, and IPD primarily affects basal ganglia nodes; both conditions disrupt the cerebellum-basal ganglia-cortical network. Moreover, functional connectome parameters showed outstanding value in the differential diagnosis of early MSA-P and IPD.

Detection of mild cognitive impairment in Parkinson's disease using gradient boosting decision tree models based on multilevel DTI indices.

BACKGROUND: Cognitive dysfunction is the most common non-motor symptom in Parkinson's disease (PD), and timely detection of a slight cognitive decline is crucial for early treatment and prevention of dementia. This study aimed to build a machine learning model based on intra- and/or intervoxel metrics extracted from diffusion tensor imaging (DTI) to automatically classify PD patients without dementia into mild cognitive impairment (PD-MCI) and normal cognition (PD-NC) groups. METHODS: We enrolled PD patients without dementia (52 PD-NC and 68 PD-MCI subtypes) who were assigned to the training and test datasets in an 8:2 ratio. Four intravoxel metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), and two novel intervoxel metrics, local diffusion homogeneity (LDH) using Spearman's rank correlation coefficient (LDHs) and Kendall's coefficient concordance (LDHk), were extracted from the DTI data. Decision tree, random forest, and eXtreme gradient boosting (XGBoost) models based on individual and combined indices were built for classification, and model performance was assessed and compared via the area under the receiver operating characteristic curve (AUC). Finally, feature importance was evaluated using SHapley Additive exPlanation (SHAP) values. RESULTS: The XGBoost model based on a combination of the intra- and intervoxel indices achieved the best classification performance, with an accuracy of 91.67%, sensitivity of 92.86%, and AUC of 0.94 in the test dataset. SHAP analysis showed that the LDH of the brainstem and MD of the right cingulum (hippocampus) were important features. CONCLUSIONS: More comprehensive information on white matter changes can be obtained by combining intra- and intervoxel DTI indices, improving classification accuracy. Furthermore, machine learning methods based on DTI indices can be used as alternatives for the automatic identification of PD-MCI at the individual level.

Study on the Interactions Between Cisplatin and Cadherin by Fluorescence Spectrometry and Atomic Force Microscopy.

Cisplatin is an important platinum drug in cancer chemotherapy in clinical practice. It is well established that the main target of cisplatin is nuclear DNA. However, recent studies have demonstrated that platinum drugs may act on some important functional proteins in the human body. E-cadherin is a newly discovered glycoprotein that has been regarded as an important sign of the occurrence and development of some tumors. This study examines the interactions between cisplatin and E-cadherin by fluorescence spectrometry and atomic force microscopy (AFM). The fluorescence spectrometry results indicated that cisplatin can efficiently quench the fluorescence of E-cadherin. The calculated binding constant Kb was 3.20 × 106 (25 ℃), 1.36 × 106(31 ℃), and 8.22 × 105 L mol-1 (37 ℃). These results reveal that the fluorescence quenching effect of cisplatin on E-cadherin is static quenching. The obtained thermodynamic parameters ΔH < 0, ΔS < 0, and ΔG < 0, indicate that the binding of cisplatin on E-cadherin is a spontaneous process dominated by hydrogen bonds and Van der Waals forces. The AFM results revealed that E-cadherins are interlaced with each other to form a spherical-chain structure. The addition of cisplatin can significantly disrupt the interlaced structure of the E-cadherin molecules.

B13, a well-tolerated inhibitor of hedgehog pathway, exhibited potent anti-tumor effects against colorectal carcinoma in vitro and in vivo.

Abnormal activation of Hedgehog (Hh) signaling pathway mediates the genesis and progression of various tumors [1]. Currently, three drugs targeting the Hh signaling component Smoothened (Smo) have been marketed for the clinical treatment of basal cell tumors or acute myeloid leukemia. However, drug resistance is a common problem in those drugs, so the study of Smo inhibitors that can overcome drug resistance has important guiding significance for clinical adjuvant drugs. MTT assay, clone formation assay and EdU assay were used to detect the proliferation inhibitory activity of the drugs on tumor cells. The effect of B13 on cell cycle and apoptosis were detected by flow cytometry. An acute toxicity test was used to detect the toxicity of B13 in vivo, and xenograft tumor model was used to detect the efficacy of B13 in vivo. The binding of B13 to Smo was studied by BODIPY-cyclopamine competitive binding assay and molecular docking. The effect of B13 on the expression and localization of downstream target gene Gli1/2 of Smo was investigated by Western Blot and immunofluorescence assay. SmoD473H mutant cell line was constructed to study the effect of B13 against drug resistance. (1) B13 had the strongest inhibitory activity against colorectal cancer cells. (2) B13 can effectively inhibit the clone formation and EdU positive rate of colon cancer cells. (3) B13 can block the cell cycle in the G2/M phase and cell apoptosis. (4) B13 has low toxicity in vivo, and its efficacy in vivo is better than that of the Vismodegib. (5) Molecular docking and BODIPY-cyclopamine experiments showed that B13 could bind to Smo protein. (6) B13 can inhibit the protein expression of Gli1, the downstream of Smo, and inhibit its entry into the nucleus. (7) B13 could inhibit the expression of Gli1 in the HEK293 cells with SmoD473H, and the molecular docking results showed that B13 could bind SmoD473H protein. B13 with the best anti-tumor activity was screened out by MTT assay. In vitro, pharmacodynamics experiments showed that B13 could effectively inhibit the proliferation and metastasis of colorectal cancer cells, induce cell cycle arrest, and induce cell apoptosis. In vivo pharmacodynamics experiments showed that B13 was superior to Vismodegib in antitumor activity and had low toxicity in vivo. Mechanism studies have shown that B13 can bind Smo protein, inhibit the expression of downstream Gli1 and its entry into the nucleus. Notably, B13 overcomes resistance caused by SmoD473H mutations.

Recombinant Klotho attenuates IFNγ receptor signaling and SAMHD1 expression through blocking NF-κB translocation in glomerular mesangial cells.

Interferon gamma (IFNγ) is a cytokine implicated in the pathogenesis of autoimmune diseases. SAM and HD domain-containing protein 1 (SAMHD1) is an IFNγ-inducible protein that modulates cellular dNTP levels. Mutations in the human SAMHD1 gene cause Aicardi-Goutières (AG) syndrome, an autoimmune disease sharing similar clinical features with systemic lupus erythematosus (SLE). Klotho is an anti-inflammatory protein which suppresses aging through multiple mechanisms. Implication of Klotho in autoimmune response is identified in rheumatologic diseases such as SLE. Little information exists regarding the effect of Klotho in lupus nephritis, one of the prevalent symptoms of SLE. The present study verified the effect of IFNγ on SAMHD1 and Klotho expression in MES-13 glomerular mesangial cells, a special cell type in glomerulus that is critically involved in lupus nephritis. IFNγ upregulated SAMHD1 expression in MES-13 cells through the Janus kinase-signal transducer and activator of transcription 1 (JAK-STAT1) and the nuclear factor kappa B (NFκB) signaling pathways. IFNγ decreased Klotho protein expression in MES-13 cells. Treatment of MES-13 cells with recombinant Klotho protein inhibited SAMHD1 expression by blocking IFNγ-induced NFκB nuclear translocation, but showed no effect on JAK-STAT1 signaling. Collectively, our findings support the protective role of Klotho in attenuating lupus nephritis through the inhibition of IFNγ-induced SAMHD1 expression and IFNγ downstream signaling in MES-13 cells.

Human umbilical-cord-derived mesenchymal stem cells in combination with rapamycin reduce cartilage degradation via inhibition of the AKT/mTOR signaling pathway.

BACKGROUND AND AIMS: Mesenchymal stem cell (MSC) therapy is a promising strategy for treating osteoarthritis (OA). However, the inflammatory microenvironment, apoptosis of transplanted cells, and shear forces during direct injection limit the therapeutic efficacy. This study aimed to explore the role of rapamycin combined with human umbilical-cord-derived mesenchymal stem cells (hUMSCs) in OA rabbits in vivo. METHODS: OA rabbits received an intra-articular injection of a collagenase solution. Gross observations, X-ray examinations, and histological examinations were performed to detect cartilage degradation levels. The fluorescent membrane dye DiR was used to label hUMSCs. In the combination therapy group, rapamycin was injected into the rabbit knee joint one day post the intra-articular injection of hUMSCs. Bioinformatics and transcriptome profiling of the knee meniscus were used to evaluate the potential molecular mechanisms of the combination therapy. RESULTS: Our study shows that rapamycin combined with hUMSCs significantly ameliorated OA severity in vivo, enhancing matrix synthesis and promoting cartilage repair. The combination therapy was more efficient than rapamycin or hUMSC treatment alone. Moreover, bioinformatics and transcriptomic analyses revealed that combination therapy might enhance autophagy in chondrocytes, partially by inhibiting the mTOR pathway. CONCLUSIONS: Our study indicates that the combination therapy of rapamycin and hUMSCs may promote cartilage repair in OA rabbits through the mTOR pathway and offers a novel approach for OA therapy. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our study provides new evidence to support the use of hUMSCs in combination with rapamycin as a potential candidate for OA treatment.

A Financial Management Platform Based on the Integration of Blockchain and Supply Chain.

Internet of Things (IoT) finance extends financial services to the whole physical commodity society with the help of IoT technology to realize financial automation and intelligence. However, the security of IoT finance still needs to be improved. Blockchain has the characteristics of decentralization, immutability, faster settlement, etc., and has been gradually applied to the field of IoT finance. Blockchain is also considered to be an effective way to resolve the problems of the traditional supply chain finance industry, such as the inability to transmit core enterprise credit, the failure of full-chain business information connections and the difficulty of clearing and settlement. Supply chain finance allows the strongest enterprise in the supply chain to apply for credit guarantee from the bank to obtain bank loans, and use the funds for circulation in the supply chain to ensure that each enterprise in the whole supply chain can obtain working capital to realize profits, so as to maximize common interests. In this paper, a financial management platform based on the integration of blockchain and supply chain has been designed and implemented. Blockchain is used to integrate supply chain finance to synchronize the bank account payment system, realize the automatic flow of funds, process supervision and automatically settle account periods based on smart contracts. The four functional modules of the system are designed using unified modeling language (UML), and the model view controller (MVC) architecture is selected as the main architecture of the system. The results of the system test show that the proposed platform can effectively improve the system security, and can use the information in the blockchain to provide multi-level financing services for enterprises in supply chain finance.

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Since December 2019, coronavirus disease 2019 (COVID-19) has been rapidly spreading worldwide and affecting the physical and mental health of the general population. It may have even more serious potential harm to children with autism spectrum disorder (ASD). This paper provides a literature review on the psychological and behavioral problems experienced by children with ASD during the COVID-19 epidemic, as well as the factors influencing these issues. The findings of this review can serve as a basis for clinical research on ASD children.

Unilaterally disrupted structural and functional connectivity of the fronto-limbic system in idiopathic hypogonadotropic hypogonadism.

OBJECTIVE: Idiopathic hypogonadotropic hypogonadism (IHH) is rare and can either be associated with normal or defective olfactory sensation, classified as normosmic IHH (nIHH) or Kallmann syndrome (KS). We do not yet understand the central processing pathways in the olfactory system. We aimed to compare the resting-state structural and functional connectivity (FC) of olfactory neural pathways in patients with IHH. We hypotheses that alterations of structural connectivity and FC may exist in the olfactory cortex pathways in IHH patients. DESIGN: STRUCTURAL AND FUNCTIONAL CONNECTIVITY DATA RESULTS BETWEEN TWO GROUPS WERE ANALYZED: Patients: Twenty-five IHH patients (13 nIHH patients and 12 KS patients) were recruited from the Department of Endocrinology and were assessed. A total of 25 age-matched healthy male controls were recruited from the community. MEASUREMENTS: All subjects underwent diffusion tensor imaging and functional magnetic resonance imaging (fMRI) scans. Structural and functional connectivity data analyses were then performed. Pearson's correlation analyses were performed to investigate the correlations between the fractional anisotropy (FA) value and FC strength, showing significant differences among the three groups separately. RESULTS: Compared with the HC group, FA value in the right uncinate fasciculus (UF) decreased significantly in the IHH group. The olfactory cortex FC values of the right gyrus rectus, orbitofrontal cortex (OFC) and right middle temporal gyrus in the IHH group were decreased compared with those in the HC group. Moreover, there were significant negative correlations between right UF FA and olfactory cortex-FC to both the gyrus rectus and OFC within the HC group (p < .05). CONCLUSION: Our findings suggest that alterations of structural and FC support the presence of neurobiological disruptions in IHH patients, particularly a specific structural-functional asymmetry disruption may exist in the olfactory cortex pathways in IHH patients.

Assessing the impact of green nudges on ozone concentration: Evidence from China's night refueling policy.

Ozone (O3) pollution poses health risks and premature mortality, and gas stations are one of the largest sources of urban volatile organic compounds (VOCs, the main precursor to O3). This paper investigates whether the government's call for night refueling, which can be regarded as a green nudge, can guide changes in consumer behavior and consequently improve environmental quality. Using a difference-in-differences (DID) estimation and weekly monitoring site air quality panel data, we analyze the effect of the Night Refueling Preferential Policy on O3 concentrations. We find that the policy can reduce O3 concentrations by 10% by encouraging consumers to refuel at night. The reduction in O3 has brought great benefits to human health, leading to a 4-5‰ reduction in non-accidental mortality and a 6-8‰ reduction in cardiovascular mortality in Jiangsu province. The economic benefits of this policy would be approximately 62-189 billion Chinese Yuan (CNY) if it were implemented nationwide. The findings of this study suggest that the government can influence consumer behavior to promote environmental quality.

Pigment of Ceiba speciosa (A. St.-Hil.) Flowers: Separation, Extraction, Purification and Antioxidant Activity.

In this work, the extraction procedure of a natural pigment from the flower of Ceiba speciosa (A. St.-Hil.) was optimized by response surface methodology. It is the first time that the extraction of the flower pigment of C. speciosa (FPCS) has been reported, along with an evaluation of its stability and biological activity under various conditions, and an exploration of its potential use as a food additive and in medicine. Specifically, the effects of ethanol concentration, solid-liquid ratio, temperature and time on the extraction rate of FPCS were determined using a Box-Behnken design. The optimum extraction conditions for FPCS were 75% ethanol with a solid-liquid ratio of 1:75 mg/mL) at 66 °C for 39 min. The purification of FPCS using different macroporous resins showed that D101 performed best when the initial mass concentration of the injection solution was 1.50 mg/mL, resulting in a three-fold increase in color value. The yield of dry flowers was 9.75% of fresh petals and the FPCS extraction efficiency was 43.2%. The effects of light, solubility, pH, temperature, sweeteners, edible acids, redox agents, preservatives and metal ions on FPCS were also investigated. Furthermore, the characteristics of FPCS were determined by spectrophotometry at a specific wavelength using the Lambert-Beer law to correlate the mass of FPCS with its absorbance value. An acute toxicological test performed according to Horne's method showed that FPCS is a non-toxic extract and thus may be used as a food additive or in other ingestible forms. Finally, western blotting showed that FPCS prevents lipopolysaccharide-induced hippocampal oxidative stress in mice. The study suggests that FPCS may function as an antioxidant with applications in the food, cosmetics and polymer industries.

Enhanced antitumor efficacy by combining afatinib with MDV3100 in castration-resistant prostate cancer.

Background: Patients with prostate cancer often develop resistance to androgen deprivation therapy, a condition called castration-resistant prostate cancer (CRPC). Enzalutamide (MDV3100) can prolong the survival of patients with CRPC after chemotherapy, but ∼50% of patients eventually relapse and develop resistance to MDV3100. Thus, it is necessary to explore new treatment methods to improve the therapeutic effect of MDV3100. Tyrosine kinases play an essential role in the pathogenesis of CRPC. Methods: MTT assay was used to detect the inhibitory effects of MDV3100 and tyrosine kinase inhibitor on prostate cancer cells. CompuSyn version 1.0 was used to calculate the combination index (CI) values using the Chou-Talalay method. Clone formation and EdU assay were used to detect the effect of afatinib combined with MDV3100 on the proliferation of 22Rv1 cells. RT-qPCR and Western blot were used to explore the mechanism of drug combination. The aim of the present study was to determine the effects of several tyrosine kinase inhibitors (TKIs) when used in combination with MDV3100 in vitro. Results: The results demonstrated that TKIs combined with MDV3100 exerted a synergistic effect on a variety of PCa cells. Afatinib combined with MDV3100 could suppress the proliferation and migration of 22RV1 cells, as well as cause their cell cycle arrest and apoptosis. Mechanistically, afatinib effectively reduced the protein expression levels of HER2 and HER3 and inhibited EGFR phosphorylation, thereby enhancing the effect of MDV3100 and suppressing CRPC. Conclusions: These findings suggested that afatinib treatment improved the effect of MDV3100 on 22RV1 cells, highlighting this drug as a potential therapeutic strategy for patients with CRPC.

Altered resting-state functional network connectivity in profound sensorineural hearing loss infants within an early sensitive period: A group ICA study.

Data from both animal models and deaf children provide evidence for that the maturation of auditory cortex has a sensitive period during the first 2-4 years of life. During this period, the auditory stimulation can affect the development of cortical function to the greatest extent. Thus far, little is known about the brain development trajectory after early auditory deprivation within this period. In this study, independent component analysis (ICA) technique was used to detect the characteristics of brain network development in children with bilateral profound sensorineural hearing loss (SNHL) before 3 years old. Seven resting-state networks (RSN) were identified in 50 SNHL and 36 healthy controls using ICA method, and further their intra-and inter-network functional connectivity (FC) were compared between two groups. Compared with the control group, SNHL group showed decreased FC within default mode network, while enhanced FC within auditory network (AUN) and salience network. No significant changes in FC were found in the visual network (VN) and sensorimotor network (SMN). Furthermore, the inter-network FC between SMN and AUN, frontal network and AUN, SMN and VN, frontal network and VN were significantly increased in SNHL group. The results implicate that the loss and the compensatory reorganization of brain network FC coexist in SNHL infants. It provides a network basis for understanding the brain development trajectory after hearing loss within early sensitive period.

Study of the effects of rabbit scleral fibroblasts on cellular biomechanical properties and MMP-2 expression using two modes of riboflavin/ultraviolet A wave collagen cross-linking.

OBJECTIVE: The aim of this study is to evaluate the cellular biomechanical properties and MMP-2 expression changes in rabbit scleral fibroblasts using two modes of riboflavin and ultraviolet A (UVA) collagen cross-linking (CXL). METHODS: Twenty-four New Zealand white rabbits were randomly divided into two groups, A and B. The left eye was chosen for the experimental group and the right eye for the control group. In group A, the eyes were irradiated for 30 min, with a power density of 3.0 mW/cm2. In group B, the eyes were irradiated for 9 min, with a power density of 10.0 mW/cm2. One week after CXL, full-field electroretinography was performed. Sixty days after CXL, the rabbits were sacrificed, and scleral fibroblasts were extracted from the CXL-treated sclera area and corresponding parts of control sclera and cultured. Cellular biomechanical properties were evaluated using the micropipette aspiration technique, and the MMP-2 protein expression was determined by Western blot analysis. RESULTS: There was no statistical difference in the amplitude and latency of the dark adaptation 3.0 and light adaptation 3.0 between the CXL and control eyes of groups A and B (P > 0.05). Compared with the control groups, the Young's modulus of the fibroblasts and apparent viscosity of the experimental eyes in groups A and B were increased after CXL (P < 0.05), but there was no significant difference between the two groups under different irradiation modes (P > 0.05). The MMP-2 expression in scleral fibroblasts from experimental eyes was significantly higher than that in scleral fibroblasts from control eyes in groups A and B. Under the two different irradiation modes, the MMP-2 expression in the scleral fibroblasts from experimental eyes in group A was significantly higher than that in the scleral fibroblasts from experimental eyes in group B. CONCLUSION: The riboflavin-UVA scleral CXL conducted in two different modes produced no significant side effects on the retina and could strengthen the cell biomechanical properties as well as increase the MMP-2 expression of scleral fibroblasts significantly.

Highly efficient and controllable photoluminescence emission on a suspended MoS2-based plasmonic grating.

Being a new class of materials, transition metal dichalcogenides are paving the way for applications in atomically thin optoelectronics. However, the intrinsically weak light-matter interaction and the lack of manipulation ability has lead to poor light emission and tunable behavior. Here, we investigate the fluorescence characteristic of monolayer molybdenum disulfide on a metal narrow-slit grating, where a highly efficient, 471 times photoluminescence enhancement are realized, based on the hybrid surface plasmon polaritons resonances and the decreased influence of substrate. Moreover, the emitted intensity and polarization are controllable due to the polarization-dependent characteristic and anisotropy of grating. The manipulations of light-matter interactions in this special system provide a new insight into the fluorescent emission process and open a new avenue for high-performance low dimensional materials devices designs.