The matching rule of Panum’s limiting case and its influencing factors

IntroductionPanum’s limiting case is one of the typical configurations of monocular occlusion region. The matching rule of Panum’s limiting case is the key to understanding how monocular occlusion region produces stereopsis. There are currently two main views on the matching rule of Panum’s limiting case, namely double fusion and uniqueness constraint. This paper further discusses its matching mechanism on the basis of previous studies.MethodsIn this study, fold line Panum’s stimuli were used to study the matching rule of Panum’s limiting case. In Experiment 1, fixation position was adopted to present the stimulus in a short time to explore the matching rules in Panum’s limiting case. In Experiment 2, the effect of fixation position on Panum’s limiting case matching results was further investigated.ResultsThe results of Experiment 1 show that when stimuli are presented in a short period of time, the reported result that a single feature in one eye may be matched alternately with two features in the other eye. This matching rule is called “fast alternative matching” in this article. The results of Experiment 2 results show that the position of the fixation could affect the matching result of participants.ConclusionIn conclusion, the matching rule of Panum’s limiting case is fast alternative matching, and the matching result is related to the attention state of the participant. These results not only provide a new perspective for matching rules in Panum’s limiting case, but also show that depth perception results in stereopsis can be influenced by top-down cognitive processing. This study provides a theoretical basis for studying the formation of stereopsis in the monocular region to a certain extent. In summary, the matching rule of Panum’s limiting case is fast alternative matching. In previous studies, the perceived result of double fusion may be caused by fast alternative matching. Also, the matching results are related to the participant’s state of attention, which suggests that the depth perception results of stereopsis are influenced by top-down cognitive processing

Label-free cell phenotypic assessment of the molecular mechanism of action of epidermal growth factor receptor inhibitors

Epidermal growth factor receptor (EGFR) is the target of several clinically approved tyrosine kinase inhibitor (TKI) drugs including gefitinib and erlotinib in the treatment of cancer. Multiple mechanisms have been implicated in the clinical features of these drugs. However, little is known about the molecular mechanism of action of these drugs at the whole cell level. Here we applied a label-free biosensor-enabled dynamic mass redistribution (DMR) assay to assess the molecular mechanism of action of three EGFR inhibitors, gefitinib, erlotinib and AG1478, to alter the EGFR signaling in A431 and HT-29, two native cancer cell lines expressing the EGFR. The whole-cell DMR assays with the persistent inhibitor treatment showed that all inhibitors dose-dependently inhibited the EGFR signaling in both cell lines, but generally displayed higher potency in A431 than HT-29 cells. The DMR assays with the inhibitor washout showed that the washout unexpectedly increased the potency of gefitinib and AG-1478 to inhibit the EGFR signaling in A431, but slightly decreased the potency of all three inhibitors in HT29. The DMR assays under microfluidics showed that the removal of the inhibitors using buffer perfusion resulted in a timedependent recovery of EGF signaling that is slower in A431 than HT-29 cells. In contrast, DMR assays under microfluidics showed that the removal of reversible competitive antagonists led to the full recovery of the signalling of two distinct G protein-coupled receptors (GPCRs), the beta(2)-adrenergic receptor in A431 and the GPR35 in HT-29 cells. Together, our results suggest that for EGFR inhibitors their uptake and retention, rather than binding kinetics, dominate their label-free cell phenotypic efficacy; however, for GPCR antagonists the binding characteristics are critical to the inhibitory effects. This study also implicates the potential of DMR assays under different simulation conditions for elucidating the cell phenotypic pharmacology, in particular transporter-related drug resistance, of kinase inhibitor drugs

Transcriptional regulation by the estrogen receptor of antioxidative stress enzymes and its functional implications

We previously reported that antiestrogen-liganded estrogen receptor b (ERb) transcriptionally activates the major detoxifying enzyme quinone reductase (QR) (NAD(P)H:-quinone oxidoreductase). Our studies also indicate that upregulation of QR, either by overexpression or induction by tamoxifen, can protect breast cells against oxidative DNA damage caused by estrogen metabolites. We now report on the upregulation of glutathione S-transferases Pi (GST-Pi) and gamma-glutamylcysteine synthetase heavy subunit (GCSh) expression by antiestrogens. Studies indicate the regulation of GST-Pi and GCSh transcriptional activity by ER. While ER regulation is mediated by an electrophile response element (EpRE), we identified mechanistic differences in the involvement of other transcription factors. Regardless of these differences, ERb-mediated regulation of GST-Pi and GCSh point towards an important role for ERb in cellular protection against oxidative stress. A protective role is supported by our observation of inhibition of estrogeninduced DNA damage upon upregulation of GST-Pi and GCSh expression

Implications of inflammatory cell death-related IFNG and co-expressed RNAs (AC006369.1 and CCR7) in breast carcinoma prognosis, and anti-tumor immunity

Objective: Interferon-γ (IFN-γ) encoded by IFNG gene is a pleiotropic molecule linked with inflammatory cell death mechanisms. This work aimed to determine and characterize IFNG and co-expressed genes, and to define their implications in breast carcinoma (BRCA).Methods: Transcriptome profiles of BRCA were retrospectively acquired from public datasets. Combination of differential expression analysis with WGCNA was conducted for selecting IFNG-co-expressed genes. A prognostic signature was generated through Cox regression approaches. The tumor microenvironment populations were inferred utilizing CIBERSORT. Epigenetic and epitranscriptomic mechanisms were also probed.Results: IFNG was overexpressed in BRCA, and connected with prolonged overall survival and recurrence-free survival. Two IFNG-co-expressed RNAs (AC006369.1, and CCR7) constituted a prognostic model that acted as an independent risk factor. The nomogram composed of the model, TNM, stage, and new event owned the satisfying efficacy in BRCA prognostication. IFNG, AC006369.1, and CCR7 were closely linked with the tumor microenvironment components (e.g., macrophages, CD4/CD8 T cells, NK cells), and immune checkpoints (notably PD1/PD-L1). Somatic mutation frequencies were 6%, and 3% for CCR7, and IFNG, and high amplification potentially resulted in their overexpression in BRCA. Hypomethylated cg05224770 and cg07388018 were connected with IFNG and CCR7 upregulation, respectively. Additionally, transcription factors, RNA-binding proteins, and non-coding RNAs possibly regulated IFNG and co-expressed genes at the transcriptional and post-transcriptional levels.Conclusion: Collectively, our work identifies IFNG and co-expressed genes as prognostic markers for BRCA, and as possible therapeutic targets for improving the efficacy of immunotherapy

Inhibition of Osteoclastogenesis and Bone Resorption in vitro and in vivo by a prenylflavonoid xanthohumol from hops

Excessive RANKL signaling leads to superfluous osteoclast formation and bone resorption, is widespread in the pathologic bone loss and destruction. Therefore, targeting RANKL or its signaling pathway has been a promising and successful strategy for this osteoclast-related diseases. In this study, we examined the effects of xanthohumol (XN), an abundant prenylflavonoid from hops plant, on osteoclastogenesis, osteoclast resorption, and RANKL-induced signaling pathway using both in vitro and in vivo assay systems. In mouse and human, XN inhibited osteoclast differentiation and osteoclast formation at the early stage. Furthermore, XN inhibited osteoclast actin-ring formation and bone resorption in a dose-dependent manner. In ovariectomized-induced bone loss mouse model and RANKL-injection-induced bone resorption model, we found that administration of XN markedly inhibited bone loss and resorption by suppressing osteoclast activity. At the molecular level, XN disrupted the association of RANK and TRAF6, resulted in the inhibition of NF-κB and Ca(2+)/NFATc1 signaling pathway during osteoclastogenesis. As a results, XN suppressed the expression of osteoclastogenesis-related marker genes, including CtsK, Nfatc1, Trap, Ctr. Therefore, our data demonstrated that XN inhibits osteoclastogenesis and bone resorption through RANK/TRAF6 signaling pathways. XN could be a promising drug candidate in the treatment of osteoclast-related diseases such as postmenopausal osteoporosis

Label-Free Phenotypic Profiling Identified D-Luciferin as a GPR35 Agonist

Fluorescent and luminescent probes are essential to both in vitro molecular assays and in vivo imaging techniques, and have been extensively used to measure biological function. However, little is known about the biological activity, thus potential interferences with the assay results, of these probe molecules. Here we show that D-luciferin, one of the most widely used bioluminescence substrates, is a partial agonist for G protein-coupled receptor-35 (GPR35). Label-free phenotypic profiling using dynamic mass redistribution (DMR) assays showed that D-luciferin led to a DMR signal in native HT-29 cells, whose characteristics are similar to those induced by known GPR35 agonists including zaprinast and pamoic acid. DMR assays further showed that D-luciferin is a partial agonist competitive to several known GPR35 agonists and antagonists. D-luciferin was found to cause the phosphorylation of ERK that was suppressed by known GPR35 antagonists, and also result in β-arrestin translocation signal but with low efficacy. These results not only suggest that D-luciferin is a partial agonist of GPR35, but also will evoke careful interpretation of biological data obtained using molecular and in vivo imaging assays when these probe molecules are used

The Three Catecholics Benserazide, Catechol and Pyrogallol are GPR35 Agonists

Nearly 1% of all clinically used drugs are catecholics, a family of catechol-containing compounds. Using label-free dynamic mass redistribution and Tango β-arrestin translocation assays, we show that several catecholics, including benserazide, catechol, 3-methoxycatechol, pyrogallol, (+)-taxifolin and fenoldopam, display agonistic activity against GPR35

Tyrphostin analogs are GPR35 agonists

AbstractGPR35 is an orphan G protein-coupled receptor that is not well-characterized. Here we employ dynamic mass redistribution (DMR) assays to discover new GPR35 agonists. DMR assays identified tyrphostin analogs as GPR35 agonists, which were confirmed with receptor internalization, Tango β-arrestin translocation, and extracellular-signal-regulated kinase phosphorylation assays. These agonists provide pharmacological tools to study the biology and function of GPR35