Structure-Guided Discovery of PD-1/PD-L1 Interaction Inhibitors: Peptide Design, Screening, and Optimization via Computation-Aided Phage Display Engineering.

Cancer immunotherapy harnesses the immune system to combat tumors and has emerged as a major cancer treatment modality. The PD-1/PD-L1 immune checkpoint modulates interactions between tumor cells and T cells and has been extensively targeted in cancer immunotherapy. However, the monoclonal antibodies known to target this immune checkpoint have considerable side effects, and novel PD-1/PD-L1 inhibitors are therefore required. Herein, a peptide inhibitor to disrupt PD-1/PD-L1 interactions was designed through structure-driven phage display engineering coupled to computational modification and optimization. BetaPb, a novel peptide library constructed by using the known structure of PD-1/PD-L, was used to develop inhibitors against the immune checkpoint, and specific peptides with high affinity toward PD-1 were screened through enzyme-linked immunosorbent assays, homogeneous time-resolved fluorescence, and biolayer interferometry. A potential inhibitor, B8, was preliminarily screened through biopanning. The binding affinity of B8 toward PD-1 was confirmed through computation-aided optimization. Assessment of B8 variants (B8.1, B8.2, B8.3, B8.4, and B8.5) demonstrated their attenuation of PD-1/PD-L1 interactions. B8.4 exhibited the strongest attenuation efficiency at a half-maximal effective concentration of 0.1 µM and the strongest binding affinity to PD-1 (equilibrium dissociation constant = 0.1 µM). B8.4 outperformed the known PD-1/PD-L1 interaction inhibitor PL120131 in disrupting PD-1/PD-L1 interactions, revealing that B8.4 has remarkable potential for modification to yield an antitumor agent. This study provides valuable information for the future development of peptide-based drugs, therapeutics, and immunotherapies for cancer.

Improving Compressed Video Using Single Lightweight Model with Temporal Fusion Module.

Video compression algorithms are commonly used to reduce the number of bits required to represent a video with a high compression ratio. However, this can result in the loss of content details and visual artifacts that affect the overall quality of the video. We propose a learning-based restoration method to address this issue, which can handle varying degrees of compression artifacts with a single model by predicting the difference between the original and compressed video frames to restore video quality. To achieve this, we adopted a recursive neural network model with dilated convolution, which increases the receptive field of the model while keeping the number of parameters low, making it suitable for deployment on a variety of hardware devices. We also designed a temporal fusion module and integrated the color channels into the objective function. This enables the model to analyze temporal correlation and repair chromaticity artifacts. Despite handling color channels, and unlike other methods that have to train a different model for each quantization parameter (QP), the number of parameters in our lightweight model is kept to only about 269 k, requiring only about one-twelfth of the parameters used by other methods. Our model applied to the HEVC test model (HM) improves the compressed video quality by an average of 0.18 dB of BD-PSNR and -5.06% of BD-BR.

Comprehensive design method of a soft multifocal contact lens with NURBS.

This study presents a comprehensive method for designing a multifocal contact lens (MCL) with Snell's law and non-uniform rational B-spline (NURBS) curves. Instead of using thin lens approximation, general mathematical formulas have been developed to achieve the accurate coordinates of points on the anterior lens surface profile of the MCL to meet various given optical power distributions. Then the NURBS curve is adjusted to fit these data points to obtain the smooth front lens surface profile. This method not only improves the accuracy of the optical power profiles of MCLs but also reduces the spherical aberration in near/distance optical zones. The experimental results show that the power profiles of soft MCLs agree with those of the simulation results and original design requirements. The proposed method has been proven for the MCL design, and it can be feasibly applied in complex optical lens designs.

TAT-Conjugated NDUFS8 Can Be Transduced into Mitochondria in a Membrane-Potential-Independent Manner and Rescue Complex I Deficiency.

NADH dehydrogenase (ubiquinone) Fe-S protein 8 (NDUFS8) is a nuclear-encoded core subunit of human mitochondrial complex I. Defects in NDUFS8 are associated with Leigh syndrome and encephalomyopathy. Cell-penetrating peptide derived from the HIV-1 transactivator of transcription protein (TAT) has been successfully applied as a carrier to bring fusion proteins into cells without compromising the biological function of the cargoes. In this study, we developed a TAT-mediated protein transduction system to rescue complex I deficiency caused by NDUFS8 defects. Two fusion proteins (TAT-NDUFS8 and NDUFS8-TAT) were exogenously expressed and purified from Escherichia coli for transduction of human cells. In addition, similar constructs were generated and used in transfection studies for comparison. The results showed that both exogenous TAT-NDUFS8 and NDUFS8-TAT were delivered into mitochondria and correctly processed. Interestingly, the mitochondrial import of TAT-containing NDUFS8 was independent of mitochondrial membrane potential. Treatment with TAT-NDUFS8 not only significantly improved the assembly of complex I in an NDUFS8-deficient cell line, but also partially rescued complex I functions both in the in-gel activity assay and the oxygen consumption assay. Our current findings suggest the considerable potential of applying the TAT-mediated protein transduction system for treatment of complex I deficiency.

Optical design of soft multifocal contact lens with uniform optical power in center-distance zone with optimized NURBS.

This study aims to develop a new optical design method of soft multifocal contact lens (CLs) to obtain uniform optical power in large center-distance zone with optimized Non-Uniform Rational B-spline (NURBS). For the anterior surface profiles of CLs, the NURBS design curves are optimized to match given optical power distributions. Then, the NURBS in the center-distance zones are fitted in the corresponding spherical/aspheric curves for both data points and their centers of curvature to achieve the uniform power. Four cases of soft CLs have been manufactured by casting in shell molds by injection molding and then measured to verify the design specifications. Results of power profiles of these CLs are concord with the given clinical requirements of uniform powers in larger center-distance zone. The developed optical design method has been verified for multifocal CLs design and can be further applied for production of soft multifocal CLs.

Compensating additional optical power in the central zone of a multifocal contact lens forminimization of the shrinkage error of the shell mold in the injection molding process.

This study aims to develop a compensating method to minimize the shrinkage error of the shell mold (SM) in the injection molding (IM) process to obtain uniform optical power in the central optical zone of soft axial symmetric multifocal contact lenses (CL). The Z-shrinkage error along the Z axis or axial axis of the anterior SM corresponding to the anterior surface of a dry contact lens in the IM process can be minimized by optimizing IM process parameters and then by compensating for additional (Add) powers in the central zone of the original lens design. First, the shrinkage error is minimized by optimizing three levels of four IM parameters, including mold temperature, injection velocity, packing pressure, and cooling time in 18 IM simulations based on an orthogonal array L18 (21×34). Then, based on the Z-shrinkage error from IM simulation, three new contact lens designs are obtained by increasing the Add power in the central zone of the original multifocal CL design to compensate for the optical power errors. Results obtained from IM process simulations and the optical simulations show that the new CL design with 0.1 D increasing in Add power has the closest shrinkage profile to the original anterior SM profile with percentage of reduction in absolute Z-shrinkage error of 55% and more uniform power in the central zone than in the other two cases. Moreover, actual experiments of IM of SM for casting soft multifocal CLs have been performed. The final product of wet CLs has been completed for the original design and the new design. Results of the optical performance have verified the improvement of the compensated design of CLs. The feasibility of this compensating method has been proven based on the measurement results of the produced soft multifocal CLs of the new design. Results of this study can be further applied to predict or compensate for the total optical power errors of the soft multifocal CLs.

Genetic deletion or pharmacological inhibition of soluble epoxide hydrolase reduces brain damage and attenuates neuroinflammation after intracerebral hemorrhage.

BACKGROUND: Inflammatory responses significantly contribute to neuronal damage and poor functional outcomes following intracerebral hemorrhage (ICH). Soluble epoxide hydrolase (sEH) is known to induce neuroinflammatory responses via degradation of anti-inflammatory epoxyeicosatrienoic acids (EET), and sEH is upregulated in response to brain injury. The present study investigated the involvement of sEH in ICH-induced neuroinflammation, brain damage, and functional deficits using a mouse ICH model and microglial cultures. METHODS: ICH was induced by injecting collagenase in both wild-type (WT) C57BL/6 mice and sEH knockout (KO) mice. WT mice were injected intracerebroventricularly with 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), a selective sEH inhibitor, 30 min before ICH. Expression of sEH in the hemorrhagic hemisphere was examined by immunofluorescence and Western blot analysis. The effects of genetic deletion or pharmacological inhibition of sEH by AUDA on neuroinflammatory responses, EET degradation, blood-brain barrier (BBB) permeability, histological damage, and functional deficits were evaluated. The anti-inflammatory mechanism of sEH inactivation was investigated in thrombin- or hemin-stimulated cultured microglia. RESULTS: ICH induced an increase in sEH protein levels in the hemorrhagic hemisphere from 3 h to 4 days. sEH was expressed in microglia/macrophages, astrocytes, neurons, and endothelial cells in the perihematomal region. Genetic deletion of sEH significantly attenuated microglia/macrophage activation and expression of inflammatory mediators and reduced EET degradation at 1 and 4 days post-ICH. Deletion of sEH also reduced BBB permeability, matrix metalloproteinase (MMP)-9 activity, neutrophil infiltration, and neuronal damage at 1 and 4 days. Likewise, administration of AUDA attenuated proinflammatory microglia/macrophage activation and EET degradation at 1 day post-ICH. These findings were associated with a reduction in functional deficits and brain damage for up to 28 days. AUDA also ameliorated neuronal death, BBB disruption, MMP-9 activity, and neutrophil infiltration at 1 day. However, neither gene deletion nor pharmacological inhibition of sEH altered the hemorrhage volume following ICH. In primary microglial cultures, genetic deletion or pharmacological inhibition of sEH by AUDA reduced thrombin- and hemin-induced microglial activation. Furthermore, AUDA reduced thrombin- and hemin-induced P38 MAPK and NF-κB activation in BV2 microglia cultures. Ultimately, AUDA attenuated N2A neuronal death that was induced by BV2 microglial conditioned media. CONCLUSIONS: Our results suggest that inhibition of sEH may provide a potential therapy for ICH by suppressing microglia/macrophage-mediated neuroinflammation.

Analysis on multifocal contact lens design based on optical power distribution with NURBS.

This paper aims to develop and analyze the design method of multifocal contact lenses to obtain curvature continuity in the optical surfaces with the high addition (Add) powers by adjusting non-uniform rational B-spline (NURBS) curves. The paper has developed mathematical formulae to generate the optical power distributions in which the powers continuously change from either near or distant center to the opposite focal length in the periphery of the optical region with different change rates and Add power values. This developed method can efficiently adjust and optimize three parameters, including control points, weight, and knots of the NURBS, to be anterior optical lens surface profiles to adapt for these given power profiles. The result shows that the proposed contact lenses not only achieve smooth and continuous anterior optical surfaces, but also satisfy various optical power distributions with high Add power values for different pupil diameters. Then, these designs of contact lenses can be feasibly converted to the computer-aided design format for analysis and manufacture for molding or single-point diamond turning. Experimental results of this method have been tested and proven when both the power distributions of simulation of lenses and the actual machined samples match the original specified powers provided by clinical demands of a multifocal contact lens. Future integration with variant clinical demands and optimization rules of lens design can be explored for a progressive contact lens.

Treatment with TO901317, a synthetic liver X receptor agonist, reduces brain damage and attenuates neuroinflammation in experimental intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) induces a series of inflammatory processes that contribute to neuronal damage and neurological deterioration. Liver X receptors (LXRs) are nuclear receptors that negatively regulate transcriptional processes involved in inflammatory responses, but their role in the pathology following ICH remains unclear. The present study investigated the neuroprotective effects and anti-inflammatory actions of TO901317, a synthetic LXR agonist, in a model of collagenase-induced ICH and in microglial cultures. METHODS: Mice subjected to collagenase-induced ICH injury were injected with either TO901317 (30 mg/kg) or vehicle 10 min after ICH and subsequently daily for 2 days. Behavioral studies, histology analysis, and assessments of hematoma volumes, brain water content, and blood-brain barrier (BBB) permeability were performed. The protein expression of LXR-α, LXR-ß, ATP binding cassette transporter-1 (ABCA-1), and inflammatory molecules was analyzed. The anti-inflammatory mechanism of TO901317 was investigated in cultured microglia that were stimulated with either lipopolysaccharide (LPS) or thrombin. RESULTS: ICH induced an increase in LXR-α protein levels in the hemorrhagic hemisphere at 6 h whereas LXR-ß expression remained unaffected. Both LXR-α and LXR-ß were expressed in neurons and microglia in the peri-ICH region and but rarely in astrocytes. TO901317 significantly attenuated functional deficits and brain damage up to 28 days post-ICH. TO901317 also reduced neuronal death, BBB disruption, and brain edema at day 4 post-ICH. These changes were associated with marked reductions in microglial activation, neutrophil infiltration, and expression levels of inflammatory mediators at 4 and 7 days. However, TO901317 had no effect on matrix metalloproteinase-9 activity. In BV2 microglial cultures, TO901317 attenuated LPS- and thrombin-stimulated nitric oxide production and reduced LPS-induced p38, JNK, MAPK, and nuclear factor-kappa B (NF-κB) signaling. Moreover, delaying administration of TO901317 to 3 h post-ICH reduced brain tissue damage and neuronal death. CONCLUSIONS: Our results suggest that enhancing LXR activation may provide a potential therapy for ICH by modulating the cytotoxic functions of microglia.

Induction of Apoptosis in Endometrial Cancer (Ishikawa) Cells by Pogostemon cablin Aqueous Extract (PCAE).

Pogostemon cablin (PC) is a traditional herbal medicine used in the treatment of the common cold, nausea, diarrhea, and even for headaches and fever. However, the mechanisms underlying the anti-proliferative activity of PC in endometrial cancer (EC) cells have yet to be fully elucidated. This study investigated the anticancer effects of an aqueous extract of Pogostemon cablin (PCAE), specifically induced apoptosis in EC (Ishikawa) cells. Proliferation of EC cells following exposure to PCAE was assessed by an MTT assay. DNA content and the induction of cell cycle apoptosis were analyzed by flow cytometry (FACS Calibur). Protein caspase-3 and, -9 as well as AIF were investigated using Western blot. Our results demonstrate growth inhibition of Ishikawa cells by PCAE. Furthermore, caspase-3 activity caused PCAE-treated cell lines to accumulate in apoptosis. Gene expression profiling (GEP) results further suggest that, in addition to its known effects with regard to EC prevention, PCAE may also exert antitumor activity on established EC cells. Many previous studies have identified the chemo-preventive effects of natural plant materials and the potential role of these materials in chemotherapy. This current study used human EC Ishikawa cells to investigate the anti-tumor effects of PCAE in EC cells. Our results demonstrate that PCAE inhibits the growth of cancer cells and induces apoptosis, which suggests the potential applicability of PCAE as an antitumor agent.

Hepatoma-derived growth factor upregulation is correlated with prognostic factors of early-stage cervical adenocarcinoma.

Hepatoma-derived growth factor (HDGF) is a unique nuclear/growth factor that plays an important role in the progression of different types of cancer. A total of 63 patients with early-stage cervical adenocarcinoma (Cx) were enrolled in this retrospective study. The expression of HDGF was significantly increased compared with adjacent non-tumor tissue samples (p < 0.001). Moreover, elevated nuclear HDGF levels were correlated with lymph-vascular space invasion (LVSI; p < 0.05), lymph node metastasis (LNM; p < 0.001), recurrence (p < 0.001) and advanced grade (AG; p < 0.001). The growth of cervical cancer cells (Hela cells) was enhanced by HDGF treatment. The HDGF mRNA and protein level were significantly higher in malignant cervical cancer cells compared with primary ones. By adenovirus gene delivery, HDGF overexpression enhanced, whereas HDGF knockdown perturbed the tumorigenic behaviors of cervical cancer cells. HDGF overexpression is common in early-stage cervical adenocarcinoma and is involved in the carcinogenesis of cervical adenocarcinoma. Cytoplasmic HDGF expression is strongly correlated with pelvic lymph node metastasis and recurrence, indicating that HDGF may serve as a novel prognostic marker for patients with Cx.

A dual mechanisms of control account of age differences in working memory.

Age-related differences in working memory (WM) can be large, but the exact sources are unclear. We hypothesized that young adults outperform older adults on WM tasks because they use controlled attention processes to prioritize the maintenance of relevant information in WM in a proactive mode, whereas older adults tend to rely on the strength of familiarity signals to make memory decisions in a reactive mode. We used a WM task that cued participants to prioritize one item over others and presented repeated lure probes that cause errors when one is engaged in a reactive mode. Results showed that, relative to young adults with full attention available to use proactive control during the delays, older adults with full attention (and young adults with divided attention) during the delays had exaggerated error rates to repeated lure probes compared to control probes. When the amount of proactive interference was increased (by repeating stimuli across trials), older adults were able to engage in proactive control, and this eliminated their exaggerated error rate (while young adults with divided attention could not). These results provide evidence for a dual mechanisms of control account of age differences in WM. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Are latent working memory items retrieved from long-term memory?

Switching one's focus of attention between to-be-remembered items in working memory (WM) is critical for cognition, but the mechanisms by which this is accomplished are unclear. A long-term memory (LTM) account suggests that switching attention away from an item, and passively retaining and reactivating such "latent" items back into the focus of attention involves episodic LTM retrieval processes, even for delays of only a few seconds. We tested this hypothesis using a two-item, double-retrocue WM task that requires participants to switch attention away from and reactivate items followed by subsequent LTM tests for reactivated items from the initial WM task (vs. continuously retained or untested control items). We compared performance on these tests between older adults (a population with LTM deficits) and young adults with either full (Experiment 1) or divided (Experiment 2) attention during the WM delay periods. The effects of reactivating latent items, as well as ageing and divided attention, had significant effects on WM performance, but did not interact with or systematically affect subsequent LTM for reactivated versus control items on item-, location-, or associative-recognition memory judgements made with either high or low confidence. Experiment 3 confirmed that these effects did not depend on whether or not young participants were warned about the subsequent LTM tests before performing the WM task. These dissociations between WM and LTM are inconsistent with the LTM account of latent WM; they are more consistent with the dynamic processing model of WM (Current Directions in Psychological Science).

Hippocampal involvement in working memory following refreshing.

Working memory (WM) and long-term memory (LTM) tests have both overlapping and distinct neurocognitive processes. Hippocampal activity in fMRI studies-a hallmark of LTM-also occurs on WM tasks, typically during encoding or retrieval and sometimes (albeit rarely) through 'late-delay' periods. The Synaptic Theory of WM suggests that 'activity-silent' synaptic weights retain temporary, WM-relevant codes without sustained, elevated activity. The hippocampus temporarily retains item-context bindings during WM-delays that are typically 'silent' to fMRI, probably via oscillatory patterns of informational connectivity among task-relevant regions of cortex. Advancing WM theory will require modeling this dynamic interplay, as in the 'Dynamic Processing Model of WM.

Lung adenocarcinoma metastasis to paranasal sinus: A case report.

BACKGROUND: Lung cancer is often metastasized to the brain, liver, kidneys, bone, bone marrow, and adrenal glands; however, metastasis of primary lung cancer to the paranasal sinuses is extremely rare. CASE SUMMARY: In this paper, we present a case of metastatic tumors of the sinus secondary to lung adenocarcinoma. The patient was a 46-year-old woman who underwent surgical removal of lung carcinoma. Four months after the surgical removal of the lung tumor, the patient presented with epistaxis, and on investigation, the diagnosis was confirmed to be nasal sinus tumors due to metastasis of lung adenocarcinoma. CONCLUSION: Thorough investigation of patients with epistaxis and a history of lung cancer is necessary to diagnose metastatic sinus tumors. We reviewed relevant literature and found that there are no characteristic clinical or radiologic features for metastatic sinus tumors; however, the diagnosis can be confirmed by histopathological examination of biopsied tumor sample.

Recent Advances In Silicon Carbide Chemical Mechanical Polishing Technologies.

Chemical mechanical polishing (CMP) is a well-known technology that can produce surfaces with outstanding global planarization without subsurface damage. A good CMP process for Silicon Carbide (SiC) requires a balanced interaction between SiC surface oxidation and the oxide layer removal. The oxidants in the CMP slurry control the surface oxidation efficiency, while the polishing mechanical force comes from the abrasive particles in the CMP slurry and the pad asperity, which is attributed to the unique pad structure and diamond conditioning. To date, to obtain a high-quality as-CMP SiC wafer, the material removal rate (MRR) of SiC is only a few micrometers per hour, which leads to significantly high operation costs. In comparison, conventional Si CMP has the MRR of a few micrometers per minute. To increase the MRR, improving the oxidation efficiency of SiC is essential. The higher oxidation efficiency enables the higher mechanical forces, leading to a higher MRR with better surface quality. However, the disparity on the Si-face and C-face surfaces of 4H- or 6H-SiC wafers greatly increases the CMP design complexity. On the other hand, integrating hybrid energies into the CMP system has proven to be an effective approach to enhance oxidation efficiency. In this review paper, the SiC wafering steps and their purposes are discussed. A comparison among the three configurations of SiC CMP currently used in the industry is made. Moreover, recent advances in CMP and hybrid CMP technologies, such as Tribo-CMP, electro-CMP (ECMP), Fenton-ECMP, ultrasonic-ECMP, photocatalytic CMP (PCMP), sulfate-PCMP, gas-PCMP and Fenton-PCMP are reviewed, with emphasis on their oxidation behaviors and polishing performance. Finally, we raise the importance of post-CMP cleaning and make a summary of the various SiC CMP technologies discussed in this work.

Intradural lumbar disc herniation: A case report and literature review.

Study design and objection: Intradural disc herniation is a unusual disease associated with spinal surgery. The definitive diagnosis of intradural herniation depends on intraoperative findings. Summary of background data: We present the case of a 63-year-old woman with backache and left sciatica radiation for more than two months. The L2/3 laminectomy and discectomy were performed after magnetic resonance imaging (MRI) study; however, no disc rupture was noted during surgery. Follow-up lumbar spine MRI revealed one large, ruptured disc. The patient underwent revision surgery with durotomy. The large intradural disc was found and removed piece by piece. Methods Results and Conclusions: Intradural disc herniation, especially large herniation, is hard to diagnose specifically despite the progression of neuroradiologic imaging techniques. A durotomy procedure should be considered if there is a missing ruptured disc or a palpable intradural mass during surgery.

Predictability of saccadic behaviors is modified by transcranial magnetic stimulation over human posterior parietal cortex.

Predictability in the visual environment provides a powerful cue for efficient processing of scenes and objects. Recently, studies have suggested that the directionality and magnitude of saccade curvature can be informative as to how the visual system processes predictive information. The present study investigated the role of the right posterior parietal cortex (rPPC) in shaping saccade curvatures in the context of predictive and non-predictive visual cues. We used an orienting paradigm that incorporated manipulation of target location predictability and delivered transcranial magnetic stimulation (TMS) over rPPC. Participants were presented with either an informative or uninformative cue to upcoming target locations. Our results showed that rPPC TMS generally increased saccade latency and saccade error rates. Intriguingly, rPPC TMS increased curvatures away from the distractor only when the target location was unpredictable and decreased saccadic errors towards the distractor. These effects on curvature and accuracy were not present when the target location was predictable. These results dissociate the strong contingency between saccade latency and saccade curvature and also indicate that rPPC plays an important role in allocating and suppressing attention to distractors when the target demands visual disambiguation. Furthermore, the present study suggests that, like the frontal eye fields, rPPC is critically involved in determining saccade curvature and the generation of saccadic behaviors under conditions of differing target predictability.

Uncertainty and predictiveness modulate attention in human predictive learning.

[Correction Notice: An Erratum for this article was reported online in Journal of Experimental Psychology: General on Jan 14 2021 (see record 2021-07705-001). In the article, formatting for UK Research Councils funding was omitted. The author note and copyright line now reflect the standard acknowledgment of and formatting for the funding received for this article. All versions of this article have been corrected.] Attention determines which cues receive processing and are learned about. Learning, however, leads to attentional biases. In the study of animal learning, in some circumstances, cues that have been previously predictive of their consequences are subsequently learned about more than are nonpredictive cues, suggesting that they receive more attention. In other circumstances, cues that have previously led to uncertain consequences are learned about more than are predictive cues. In human learning, there is a clear role for predictiveness, but a role for uncertainty has been less clear. Here, in a human learning task, we show that cues that led to uncertain outcomes were subsequently learned about more than were cues that were previously predictive of their outcomes. This effect occurred when there were few uncertain cues. When the number of uncertain cues was increased, attention switched to predictive cues. This pattern of results was found for cues (1) that were uncertain because they led to 2 different outcomes equally often in a nonpredictable manner and (2) that were used in a nonlinear discrimination and were not predictive individually but were predictive in combination with other cues. This suggests that both the opposing predictiveness and uncertainty effects were determined by the relationship between individual cues and outcomes rather than the predictive strength of combined cues. These results demonstrate that learning affects attention; however, the precise nature of the effect on attention depends on the level of task complexity, which reflects a potential switch between exploration and exploitation of cues. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Acacetin, a flavonoid, inhibits the invasion and migration of human prostate cancer DU145 cells via inactivation of the p38 MAPK signaling pathway.

Acacetin (5,7-dihydroxy-4'-methoxyflavone), a flavonoid compound, has anti-peroxidative and anti-inflammatory effects. The effect of acacetin on antimetastasis in human prostate cancer DU-145 cells was investigated. First, the result demonstrated acacetin could exhibit an inhibitory effect on the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay, wound-healing assay, and Boyden chamber assay. Data also showed acacetin could inhibit the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) involved in the downregulation of the expressions of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and urokinase-type plasminogen activator (u-PA) at both the protein and mRNA levels. Next, acacetin significantly decreased the nuclear levels of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun. Also, the treatment with acacetin to DU145 cells also leads to a dose-dependent inhibition on the binding ability of NF-kappaB and activator protein-1 (AP-1). Furthermore, the treatment of inhibitors specific for p38 MAPK (SB203580) to DU145 cells could cause reduced expressions of MMP-2, MMP-9, and u-PA. These results showed acacetin could inhibit the invasion and migration abilities of DU145 cells by reducing MMP-2, MMP-9, and u-PA expressions through suppressing p38 MAPK signaling pathway and inhibiting NF-kappaB- or AP-1-binding activity. These findings proved acacetin might be offered further application as an antimetastatic agent.