The Critical Role of Equilibrative Nucleoside Transporter-2 in Modulating Cerebral Damage and Vascular Dysfunction in Mice with Brain Ischemia-Reperfusion.

BACKGROUND: Cerebral vascular protection is critical for stroke treatment. Adenosine modulates vascular flow and exhibits neuroprotective effects, in which brain extracellular concentration of adenosine is dramatically increased during ischemic events and ischemia-reperfusion. Since the equilibrative nucleoside transporter-2 (Ent2) is important in regulating brain adenosine homeostasis, the present study aimed to investigate the role of Ent2 in mice with cerebral ischemia-reperfusion. METHODS: Cerebral ischemia-reperfusion injury was examined in mice with transient middle cerebral artery occlusion (tMCAO) for 90 minutes, followed by 24-hour reperfusion. Infarct volume, brain edema, neuroinflammation, microvascular structure, regional cerebral blood flow (rCBF), cerebral metabolic rate of oxygen (CMRO2), and the production of reactive oxygen species (ROS) were examined following the reperfusion. RESULTS: Ent2 deletion reduced the infarct volume, brain edema, and neuroinflammation in mice with cerebral ischemia-reperfusion. tMCAO-induced disruption of brain microvessels was ameliorated in Ent2-/- mice, with a reduced expression of matrix metalloproteinases-9 and aquaporin-4 proteins. Following the reperfusion, the rCBF of the wild-type (WT) mice was quickly restored to the baseline, whereas, in Ent2-/- mice, rCBF was slowly recovered initially, but was then higher than that in the WT mice at the later phase of reperfusion. The improved CMRO2 and reduced ROS level support the beneficial effects caused by the changes in the rCBF of Ent2-/- mice. Further studies showed that the protective effects of Ent2 deletion in mice with tMCAO involve adenosine receptor A2AR. CONCLUSIONS: Ent2 plays a critical role in modulating cerebral collateral circulation and ameliorating pathological events of brain ischemia and reperfusion injury.

Chloroquine enhances the efficacy of chemotherapy drugs against acute myeloid leukemia by inactivating the autophagy pathway.

Current therapy for acute myeloid leukemia (AML) is largely hindered by the development of drug resistance of commonly used chemotherapy drugs, including cytarabine, daunorubicin, and idarubicin. In this study, we investigated the molecular mechanisms underlying the chemotherapy drug resistance and potential strategy to improve the efficacy of these drugs against AML. By analyzing data from ex vivo drug-response and multi-omics profiling public data for AML, we identified autophagy activation as a potential target in chemotherapy-resistant patients. In THP-1 and MV-4-11 cell lines, knockdown of autophagy-regulated genes ATG5 or MAP1LC3B significantly enhanced AML cell sensitivity to the chemotherapy drugs cytarabine, daunorubicin, and idarubicin. In silico screening, we found that chloroquine phosphate mimicked autophagy inactivation. We showed that chloroquine phosphate dose-dependently down-regulated the autophagy pathway in MV-4-11 cells. Furthermore, chloroquine phosphate exerted a synergistic antitumor effect with the chemotherapy drugs in vitro and in vivo. These results highlight autophagy activation as a drug resistance mechanism and the combination therapy of chloroquine phosphate and chemotherapy drugs can enhance anti-AML efficacy.

Effect of hydraulic regime on sulfur-packed bed performance: Denitrification and disproportionation.

Sulfur-packed beds (SPBs) have been increasingly incorporated into constructed wetland systems to overcome limitations in achieving satisfactory nitrate removal efficiency. However, the underlying impact of hydraulic regimes on SPB performance remains understudied. This study investigated the performance of a pilot-scale SPB, encompassing sulfur autotrophic denitrification (SAD) and sulfur disproportionation (SDP) processes, under various horizontal flow (HF) and vertical flow (VF) regimes. The HF regime exhibited superior SAD efficiency, achieving 3.1-4.4 mg-N/L of nitrate removal compared to 0.9-2.8 mg-N/L under VF regimes. However, greater sulfide production of 3.8-5.6 mg/L was observed, in contrast to only 1.5-2.3 mg/L under VF regimes when SDP occurred. Employing current computational fluid dynamics simulations could predict general regimes but lacked precision in detailing sulfur layer dynamics. In contrast, determining the spatial distribution of SAD substrates and SDP products offered a viable solution, revealing stagnate, short-circuit, and back flows. Moreover, the feasibility of an aeration approach to reduce sulfide emissions below 0.5 mg/L in case of accidental SDP occurrence was confirmed. This study offers a method for assessing detailed hydraulic regimes within SPBs. Additionally, it provides guidance on optimizing the packing of sulfur-based materials when implementing SPBs in constructed wetland systems and presents a strategy for mitigating excessive sulfide emissions.

Response of sulfur-metabolizing biofilm to external sulfide in element sulfur-based denitrification packed-bed reactor.

Dosing sulfide into the sulfur-packed-bed (S0PB) has great potential to enhance the denitrification efficiency by providing compensatory electron donors, however, the response of sulfur-metabolizing biofilm to various sulfide dosages has never been investigated. In this study, the S0PB reactor was carried out with increasing sulfide dosages by 3.6 kg/m3/d, presenting a decreasing effluent nitrate from 14.2 to 2.7 mg N/L with accelerated denitrification efficiency (k: 0.04 to 0.27). However, 6.5 mg N/L of nitrite accumulated when the sulfide dosage exceeded 0.9 kg/m3/d (optimum value). The increasing electron export contribution of sulfide a maximum of 85.5% illustrated its competition with the in-situ sulfur. Meanwhile, over-dosing sulfide caused serious biofilm expulsion with significant decreases in the total biomass, live cell population, and ATP by 90.2%, 86.7%, and 54.8%, respectively. This study verified the capacity of dosing sulfide to improve the denitrification efficiency in S0PB but alerted the negative effect of exceeded dosing.

Downregulation of c-Myc expression confers sensitivity to CHK1 inhibitors in hematologic malignancies.

Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent. We demonstrated that the downregulation of c-Myc and its signaling pathway was the common transcriptomic profiling response of sensitive HM cell lines to PY34, whereas overexpressing c-Myc could partially rescue the anticancer effect of PY34. Strikingly, we revealed the significant correlations between downregulation of c-Myc and cell sensitivity to PY34 in 17 HM cell lines and 39 patient-derived cell (PDC) samples. Thus, our results demonstrate that HMs are more sensitive to CHK1i than solid tumors, and c-Myc downregulation could represent the CHK1i efficacy in HMs.

Experimental study on the monotonic mechanical behavior of completely decomposed granite soil reinforced by disposable face-mask chips.

In response to the global outbreak of the coronavirus pandemic (COVID-19), a staggering amount of personal protective equipment, such as disposable face masks, has been used, leading to the urgent environmental issue. This study evaluates the feasibility of mask chips for the soil reinforcement, through triaxial tests on samples mixed with complete decomposed granite (CDG) and mask chips (0%, 0.3%, 0.5%, 1%, 5% by volume). The experimental results show that adding a moderate volumetric amount of mask chips (0.3%-1%) improves the soil strength, especially under high confining pressure. The optimum volumetric content of mask chips obtained by this study is 0.5%, raising the peak shear strength up to 22.3% under the confining stress of 120 kPa. When the volumetric content of mask chips exceeds the optimum value, the peak shear strength decreases accordingly. A limited amount of mask chips also increases the elastic modulus and makes the volumetric response more dilative. By contrast, excessive mask chips create additional voids and shift the strong soil-mask contacts to weak mask-mask contacts. The laser scanning microscope (LSM) and scanning electron microscope (SEM) images on the typical samples demonstrate the microstructure of mask fibers interlocking with soil particles, highly supporting the macro-scale mechanical behavior.

Activation of unfolded protein response overcomes Ibrutinib resistance in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most widespread type of non-Hodgkin lymphoma (NHL). As the most aggressive form of the DLBCL, the activated B-cell-like (ABC) subtype is often resistant to standard chemotherapies. Bruton's tyrosine kinase (BTK) inhibitor ibrutinib provides a potential therapeutic approach for the DLBCL but fails to improve the outcome in the phase III trial. In the current study, we investigated the molecular mechanisms underlying ibrutinib resistance and explored new combination therapy with ibrutinib. We generated an ibrutinib-resistant ABC-DLBCL cell line (OCI-ly10-IR) through continuous exposure to ibrutinib. Transcriptome analysis of the parental and ibrutinib-resistant cell lines revealed that the ibrutinib-resistant cells had significantly lower expression of the unfolded protein response (UPR) marker genes. Overexpression of one UPR branch-XBP1s greatly potentiated ibrutinib-induced apoptosis in both sensitive and resistant cells. The UPR inhibitor tauroursodeoxycholic acid (TUDCA) partially reduced the apoptotic rate induced by the ibrutinib in sensitive cells. The UPR activator 2-deoxy-D-glucose (2-DG) in combination with the ibrutinib triggered even greater cell growth inhibition, apoptosis, and stronger calcium (Ca2+) flux inhibition than either of the agents alone. A combination treatment of ibrutinib (15 mg·kg-1·d-1, po.) and 2-DG (500 mg/kg, po, b.i.d.) synergistically retarded tumor growth in NOD/SCID mice bearing OCI-ly10-IR xenograft. In addition, ibrutinib induced the UPR in the sensitive cell lines but not in the resistant cell lines of the DLBCL. There was also a combined synergistic effect in the primary resistant DLBCL cell lines. Overall, our results suggest that targeting the UPR could be a potential combination strategy to overcome ibrutinib resistance in the DLBCL.

Design and synthesis of new lenalidomide analogs via Suzuki cross-coupling reaction.

Lenalidomide is a cereblon modulator known for its antitumor, anti-inflammatory, and immunomodulatory properties in clinical applications. Recently, some reported lenalidomide analogs could exhibit a significant bioactivity through various modifications in the isoindolinone ring. In this study, we designed and synthesized a series of novel lenalidomide analogs on the basis of the installation of a methylene chain at the C-4 position of isoindolinone via the Suzuki cross-coupling reaction. These new compounds were further evaluated for their in vitro antiproliferative activities against two tumor cell lines (MM.1S and Mino). Specifically, compound 4c displayed the strongest antiproliferative activity against the MM.1S (IC50 = 0.27 ± 0.03 µM) and Mino (IC50 = 5.65 ± 0.58 µM) tumor cell lines. In summary, we have developed a new synthetic strategy for C-4 derivatization of lenalidomide, providing a bioactive scaffold that could be used to discover further potential antitumor lead compounds in pharmaceutical research.

Clinical value of miR-452-5p expression in lung adenocarcinoma: A retrospective quantitative real-time polymerase chain reaction study and verification based on The Cancer Genome Atlas and Gene Expression Omnibus databases.

The role and mechanism of miR-452-5p in lung adenocarcinoma remain unclear. In this study, we performed a systematic study to investigate the clinical value of miR-452-5p expression in lung adenocarcinoma. The expression of miR-452-5p in 101 lung adenocarcinoma patients was detected by quantitative real-time polymerase chain reaction. The Cancer Genome Atlas and Gene Expression Omnibus databases were joined to verify the expression level of miR-452-5p in lung adenocarcinoma. Via several online prediction databases and bioinformatics software, pathway and network analyses of miR-452-5p target genes were performed to explore its prospective molecular mechanism. The expression of miR-452-5p in lung adenocarcinoma in house was significantly lower than that in adjacent tissues (p < 0.001). Additionally, the expression level of miR-452-5p was negatively correlated with several clinicopathological parameters including the tumor size (p = 0.014), lymph node metastasis (p = 0.032), and tumor-node-metastasis stage (p = 0.036). Data from The Cancer Genome Atlas also confirmed the low expression of miR-452 in lung adenocarcinoma (p < 0.001). Furthermore, reduced expression of miR-452-5p in lung adenocarcinoma (standard mean deviations = -0.393, 95% confidence interval: -0.774 to -0.011, p = 0.044) was validated by a meta-analysis. Five hub genes targeted by miR-452-5p, including SMAD family member 4, SMAD family member 2, cyclin-dependent kinase inhibitor 1B, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon, and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta, were significantly enriched in the cell-cycle pathway. In conclusion, low expression of miR-452-5p tends to play an essential role in lung adenocarcinoma. Bioinformatics analysis might be beneficial to reveal the potential mechanism of miR-452-5p in lung adenocarcinoma.

Clinical Value of miR-101-3p and Biological Analysis of its Prospective Targets in Breast Cancer: A Study Based on The Cancer Genome Atlas (TCGA) and Bioinformatics.

BACKGROUND MiR-101-3p can promote apoptosis and inhibit proliferation, invasion, and metastasis in breast cancer (BC) cells. However, its mechanisms in BC are not fully understood. Therefore, a comprehensive analysis of the target genes, pathways, and networks of miR-101-3p in BC is necessary. MATERIAL AND METHODS The miR-101 profiles for 781 patients with BC from The Cancer Genome Atlas (TCGA) were analyzed. Gene expression profiling of GSE31397 with miR-101-3p transfected MCF-7 cells and scramble control cells was downloaded from Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) were identified. The potential genes targeted by miR-101-3p were also predicted. Gene Ontology (GO) and pathway and network analyses were constructed for the DEGs and predicted genes. RESULTS In the TCGA data, a low level of miR-101-2 expression might represent a diagnostic (AUC: 0.63) marker, and the miR-101-1 was a prognostic (HR=1.79) marker. MiR-101-1 was linked to the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), and miR-101-2 was associated with the tumor (T), lymph node (N), and metastasis (M) stages of BC. Moreover, 427 genes were selected from the 921 DEGs in GEO and the 7924 potential target genes from the prediction databases. These genes were related to transcription, metabolism, biosynthesis, and proliferation. The results were also significantly enriched in the VEGF, mTOR, focal adhesion, Wnt, and chemokine signaling pathways. CONCLUSIONS MiR-101-1 and miR-101-2 may be prospective biomarkers for the prognosis and diagnosis of BC, respectively, and are associated with diverse clinical parameters. The target genes of miR-101-3p regulate the development and progression of BC. These results provide insight into the pathogenic mechanism and potential therapies for BC.

Risk Factors of Depression Screened by Two-Sample Mendelian Randomization Analysis: A Systematic Review.

Objective: This study explored the potentially modifiable factors for depression and major depressive disorder (MDD) from the MR-Base database and further evaluated the associations between drug targets with MDD. Methods: We analyzed two-sample of Mendelian randomization (2SMR) using genetic variant depression ( n = 113,154) and MDD ( n = 208,811) from Genome-Wide Association Studies (GWAS). Separate calculations were performed with modifiable risk factors from MR-Base for 1,001 genomes. The MR analysis was performed by screening drug targets with MDD in the DrugBank database to explore the therapeutic targets for MDD. Inverse variance weighted (IVW), fixed-effect inverse variance weighted (FE-IVW), MR-Egger, weighted median, and weighted mode were used for complementary calculation. Results: The potential causal relationship between modifiable risk factors and depression contained 459 results for depression and 424 for MDD. Also, the associations between drug targets and MDD showed that SLC6A4, GRIN2A, GRIN2C, SCN10A, and IL1B expression are associated with an increased risk of depression. In contrast, ADRB1, CHRNA3, HTR3A, GSTP1, and GABRG2 genes are candidate protective factors against depression. Conclusion: This study identified the risk factors causally associated with depression and MDD, and estimated 10 drug targets with significant impact on MDD, providing essential information for formulating strategies to prevent and treat depression.

Regulation of TMEM100 expression by epigenetic modification, effects on proliferation and invasion of esophageal squamous carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy with a high morbidity and mortality rate. TMEM100 has been shown to be suppressor gene in a variety of tumors, but there are no reports on the role of TMEM100 in esophageal cancer (EC). AIM: To investigate epigenetic regulation of TMEM100 expression in ESCC and the effect of TMEM100 on ESCC proliferation and invasion. METHODS: Firstly, we found the expression of TMEM100 in EC through The Cancer Genome Atlas database. The correlation between TMEM100 gene expression and the survival of patients with EC was further confirmed through Kaplan-Meier analysis. We then added the demethylating agent 5-AZA to ESCC cell lines to explore the regulation of TMEM100 expression by epigenetic modification. To observe the effect of TMEM100 expression on tumor proliferation and invasion by overexpressing TMEM100. Finally, we performed gene set enrichment analysis using the Kyoto Encyclopaedia of Genes and Genomes Orthology-Based Annotation System database to look for pathways that might be affected by TMEM100 and verified the effect of TMEM100 expression on the mitogen-activated protein kinases (MAPK) pathway. RESULTS: In the present study, by bioinformatic analysis we found that TMEM100 was lowly expressed in EC patients compared to normal subjects. Kaplan-meier survival analysis showed that low expression of TMEM100 was associated with poor prognosis in patients with EC. Then, we found that the demethylating agent 5-AZA resulted in increased expression of TMEM100 in ESCC cells [quantitative real-time PCR (qRT-PCR) and western blotting]. Subsequently, we confirmed that overexpression of TMEM100 leads to its increased expression in ESCC cells (qRT-PCR and western blotting). Overexpression of TMEM100 also inhibited proliferation, invasion and migration of ESCC cells (cell counting kit-8 and clone formation assays). Next, by enrichment analysis, we found that the gene set was significantly enriched in the MAPK signaling pathway. The involvement of TMEM100 in the regulation of MAPK signaling pathway in ESCC cell was subsequently verified by western blotting. CONCLUSION: TMEM100 is a suppressor gene in ESCC, and its low expression may lead to aberrant activation of the MAPK pathway. Promoter methylation may play a key role in regulating TMEM100 expression.

Upper-Arm Photoplethysmographic Sensor with One-Time Calibration for Long-Term Blood Pressure Monitoring.

Wearable cuffless photoplethysmographic blood pressure monitors have garnered widespread attention in recent years; however, the long-term performance values of these devices are questionable. Most cuffless blood pressure monitors require initial baseline calibration and regular recalibrations with a cuffed blood pressure monitor to ensure accurate blood pressure estimation, and their estimation accuracy may vary over time if left uncalibrated. Therefore, this study assessed the accuracy and long-term performance of an upper-arm, cuffless photoplethysmographic blood pressure monitor according to the ISO 81060-2 standard. This device was based on a nonlinear machine-learning model architecture with a fine-tuning optimized method. The blood pressure measurement protocol followed a validation procedure according to the standard, with an additional four weekly blood pressure measurements over a 1-month period, to assess the long-term performance values of the upper-arm, cuffless photoplethysmographic blood pressure monitor. The results showed that the photoplethysmographic signals obtained from the upper arm had better qualities when compared with those measured from the wrist. When compared with the cuffed blood pressure monitor, the means ± standard deviations of the difference in BP at week 1 (baseline) were -1.36 ± 7.24 and -2.11 ± 5.71 mmHg for systolic and diastolic blood pressure, respectively, which met the first criterion of ≤5 ± ≤8.0 mmHg and met the second criterion of a systolic blood pressure ≤ 6.89 mmHg and a diastolic blood pressure ≤ 6.84 mmHg. The differences in the uncalibrated blood pressure values between the test and reference blood pressure monitors measured from week 2 to week 5 remained stable and met both criteria 1 and 2 of the ISO 81060-2 standard. The upper-arm, cuffless photoplethysmographic blood pressure monitor in this study generated high-quality photoplethysmographic signals with satisfactory accuracy at both initial calibration and 1-month follow-ups. This device could be a convenient and practical tool to continuously measure blood pressure over long periods of time.

Enhancing Prediction of Forelimb Movement Trajectory through a Calibrating-Feedback Paradigm Incorporating RAT Primary Motor and Agranular Cortical Ensemble Activity in the Goal-Directed Reaching Task.

Complete reaching movements involve target sensing, motor planning, and arm movement execution, and this process requires the integration and communication of various brain regions. Previously, reaching movements have been decoded successfully from the motor cortex (M1) and applied to prosthetic control. However, most studies attempted to decode neural activities from a single brain region, resulting in reduced decoding accuracy during visually guided reaching motions. To enhance the decoding accuracy of visually guided forelimb reaching movements, we propose a parallel computing neural network using both M1 and medial agranular cortex (AGm) neural activities of rats to predict forelimb-reaching movements. The proposed network decodes M1 neural activities into the primary components of the forelimb movement and decodes AGm neural activities into internal feedforward information to calibrate the forelimb movement in a goal-reaching movement. We demonstrate that using AGm neural activity to calibrate M1 predicted forelimb movement can improve decoding performance significantly compared to neural decoders without calibration. We also show that the M1 and AGm neural activities contribute to controlling forelimb movement during goal-reaching movements, and we report an increase in the power of the local field potential (LFP) in beta and gamma bands over AGm in response to a change in the target distance, which may involve sensorimotor transformation and communication between the visual cortex and AGm when preparing for an upcoming reaching movement. The proposed parallel computing neural network with the internal feedback model improves prediction accuracy for goal-reaching movements.

Multimodal Optical Imaging to Investigate Spatiotemporal Changes in Cerebrovascular Function in AUDA Treatment of Acute Ischemic Stroke.

Administration of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) has been demonstrated to alleviate infarction following ischemic stroke. Reportedly, the main effect of AUDA is exerting anti-inflammation and neovascularization via the inhibition of soluble epoxide hydrolase. However, the major contribution of this anti-inflammation and neovascularization effect in the acute phase of stroke is not completely elucidated. To investigate the neuroprotective effects of AUDA in acute ischemic stroke, we combined laser speckle contrast imaging and optical intrinsic signal imaging techniques with the implantation of a lab-designed cranial window. Forepaw stimulation was applied to assess the functional changes via measuring cerebral metabolic rate of oxygen (CMRO2) that accompany neural activity. The rats that received AUDA in the acute phase of photothrombotic ischemia stroke showed a 30.5 ± 8.1% reduction in the ischemic core, 42.3 ± 15.1% reduction in the ischemic penumbra (p < 0.05), and 42.1 ± 4.6% increase of CMRO2 in response to forepaw stimulation at post-stroke day 1 (p < 0.05) compared with the control group (N = 10 for each group). Moreover, at post-stroke day 3, increased functional vascular density was observed in AUDA-treated rats (35.9 ± 1.9% higher than that in the control group, p < 0.05). At post-stroke day 7, a 105.4% ± 16.4% increase of astrocytes (p < 0.01), 30.0 ± 10.9% increase of neurons (p < 0.01), and 65.5 ± 15.0% decrease of microglia (p < 0.01) were observed in the penumbra region in AUDA-treated rats (N = 5 for each group). These results suggested that AUDA affects the anti-inflammation at the beginning of ischemic injury and restores neuronal metabolic rate of O2 and tissue viability. The neovascularization triggered by AUDA restored CBF and may contribute to ischemic infarction reduction at post-stroke day 3. Moreover, for long-term neuroprotection, astrocytes in the penumbra region may play an important role in protecting neurons from apoptotic injury.

Electrosprayed Ultra-Thin Coating of Ethyl Cellulose on Drug Nanoparticles for Improved Sustained Release.

In nanopharmaceutics, polymeric coating is a popular strategy for modifying the drug release kinetics and, thus, new methods for implementing the nanocoating processes are highly desired. In the present study, a modified coaxial electrospraying process was developed to formulate an ultra-thin layer of ethyl cellulose (EC) on a medicated composite core consisting of tamoxifen citrate (TAM) and EC. A traditional single-fluid blending electrospraying and its monolithic EC-TAM nanoparticles (NPs) were exploited to compare. The modified coaxial processes were demonstrated to be more continuous and robust. The created NPs with EC coating had a higher quality than the monolithic ones in terms of the shape, surface smoothness, and the uniform size distribution, as verified by the SEM and TEM results. XRD patterns suggested that TAM presented in all the NPs in an amorphous state thanks to the fine compatibility between EC and TAM, as indicated by the attenuated total reflection (ATR)-FTIR spectra. In vitro dissolution tests demonstrated that the NPs with EC coating required a time period of 7.58 h, 12.79 h, and 28.74 h for an accumulative release of 30%, 50%, and 90% of the loaded drug, respectively. The protocols reported here open a new way for developing novel medicated nanoparticles with functional coating.

Interfering MSN-NONO complex-activated CREB signaling serves as a therapeutic strategy for triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is life-threatening because of limited therapies and lack of effective therapeutic targets. Here, we found that moesin (MSN) was significantly overexpressed in TNBC compared with other subtypes of breast cancer and was positively correlated with poor overall survival. However, little is known about the regulatory mechanisms of MSN in TNBC. We found that MSN significantly stimulated breast cancer cell proliferation and invasion in vitro and tumor growth in vivo, requiring the phosphorylation of MSN and a nucleoprotein NONO-assisted nuclear localization of phosphorylated MSN with protein kinase C (PKC) and then the phosphorylation activation of CREB signaling by PKC. Our study also demonstrated that targeting MSN, NONO, or CREB significantly inhibited breast tumor growth in vivo. These results introduce a new understanding of MSN function in breast cancer and provide favorable evidence that MSN or its downstream molecules might serve as new targets for TNBC treatment.

Inhibition of Long-Term Variability in Decoding Forelimb Trajectory Using Evolutionary Neural Networks With Error-Correction Learning.

Objective: In brain machine interfaces (BMIs), the functional mapping between neural activities and kinematic parameters varied over time owing to changes in neural recording conditions. The variability in neural recording conditions might result in unstable long-term decoding performance. Relevant studies trained decoders with several days of training data to make them inherently robust to changes in neural recording conditions. However, these decoders might not be robust to changes in neural recording conditions when only a few days of training data are available. In time-series prediction and feedback control system, an error feedback was commonly adopted to reduce the effects of model uncertainty. This motivated us to introduce an error feedback to a neural decoder for dealing with the variability in neural recording conditions. Approach: We proposed an evolutionary constructive and pruning neural network with error feedback (ECPNN-EF) as a neural decoder. The ECPNN-EF with partially connected topology decoded the instantaneous firing rates of each sorted unit into forelimb movement of a rat. Furthermore, an error feedback was adopted as an additional input to provide kinematic information and thus compensate for changes in functional mapping. The proposed neural decoder was trained on data collected from a water reward-related lever-pressing task for a rat. The first 2 days of data were used to train the decoder, and the subsequent 10 days of data were used to test the decoder. Main Results: The ECPNN-EF under different settings was evaluated to better understand the impact of the error feedback and partially connected topology. The experimental results demonstrated that the ECPNN-EF achieved significantly higher daily decoding performance with smaller daily variability when using the error feedback and partially connected topology. Significance: These results suggested that the ECPNN-EF with partially connected topology could cope with both within- and across-day changes in neural recording conditions. The error feedback in the ECPNN-EF compensated for decreases in decoding performance when neural recording conditions changed. This mechanism made the ECPNN-EF robust against changes in functional mappings and thus improved the long-term decoding stability when only a few days of training data were available.

Enhancement of Hippocampal Spatial Decoding Using a Dynamic Q-Learning Method With a Relative Reward Using Theta Phase Precession.

Hippocampal place cells and interneurons in mammals have stable place fields and theta phase precession profiles that encode spatial environmental information. Hippocampal CA1 neurons can represent the animal's location and prospective information about the goal location. Reinforcement learning (RL) algorithms such as Q-learning have been used to build the navigation models. However, the traditional Q-learning ([Formula: see text]Q-learning) limits the reward function once the animals arrive at the goal location, leading to unsatisfactory location accuracy and convergence rates. Therefore, we proposed a revised version of the Q-learning algorithm, dynamical Q-learning ([Formula: see text]Q-learning), which assigns the reward function adaptively to improve the decoding performance. Firing rate was the input of the neural network of [Formula: see text]Q-learning and was used to predict the movement direction. On the other hand, phase precession was the input of the reward function to update the weights of [Formula: see text]Q-learning. Trajectory predictions using [Formula: see text]Q- and [Formula: see text]Q-learning were compared by the root mean squared error (RMSE) between the actual and predicted rat trajectories. Using [Formula: see text]Q-learning, significantly higher prediction accuracy and faster convergence rate were obtained compared with [Formula: see text]Q-learning in all cell types. Moreover, combining place cells and interneurons with theta phase precession improved the convergence rate and prediction accuracy. The proposed [Formula: see text]Q-learning algorithm is a quick and more accurate method to perform trajectory reconstruction and prediction.