A kind of sensing scheme is theoretically proposed to efficiently tune the response range of a fiber-optic refractometer based on the adiabatic transmission of the higher-order LP11 mode. Near the cut-off condition, transmission of the LP11 mode is a strong function of the refractive index (RI) under detection; thus high sensitivity is achieved. The cut-off RI value is dependent on the waist diameter; therefore the response RI range with high sensitivity can be changed just by altering the waist diameter. Theoretical calculations reveal that the response range is effectively tuned from 1.43-1.438 to 1.35-1.365 when the waist diameter is reduced from 2.5 to 1 ?m. The proposed fiber-optic sensor is also superior when used as an absorbing sensor since the higher-order mode LP11 has a much larger power fraction in the evanescent field compared with the fundamental mode LP01 of the same fiber.
A lattice Boltzmann (LB) formulation, which is consistent with the phase-field model for two-phase incompressible fluid, is proposed to model the interface dynamics of droplet impingement. The interparticle force is derived by comparing the macroscopic transport equations recovered from LB equations with the governing equations of the continuous phase-field model. The inconsistency between the existing LB implementations and the phase-field model in calculating the relaxation time at the phase interface is identified and an approximation is proposed to ensure the consistency with the phase-field model. It is also shown that the commonly used equilibrium velocity boundary for the binary fluid LB scheme does not conserve momentum at the wall boundary and a modified scheme is developed to ensure the momentum conservation at the boundary. In addition, a geometric formulation of the wetting boundary condition is proposed to replace the popular surface energy formulation and results show that the geometric approach enforces the prescribed contact angle better than the surface energy formulation in both static and dynamic wetting. The proposed LB formulation is applied to simulating droplet impingement dynamics in three dimensions and results are compared to those obtained with the continuous phase-field model, the LB simulations reported in the literature, and experimental data from the literature. The results show that the proposed LB simulation approach yields not only a significant speed improvement over the phase-field model in simulating droplet impingement dynamics on a submillimeter length scale, but also better accuracy than both the phase-field model and the previously reported LB techniques when compared to experimental data. Upon validation, the proposed LB modeling methodology is applied to the study of multiple-droplet impingement and interactions in three dimensions, which demonstrates its powerful capability of simulating extremely complex interface phenomena.
Glioblastoma multiforme (GBM) is the most lethal and aggressive type of primary brain malignancy. Failures of the traditional therapies in treating GBMs raise the urgent requirement to develop new approaches with more responsive targets. The phenomenon of the high infiltration of tumor-associated macrophages (TAMs) into GBMs has been observed for a long time. Regardless of the limited knowledge about TAMs, the high percentage of supportive TAM in GBM tumor mass makes it possible to be a good target for GBM treatment. In this review, we discussed the unique features of TAMs in GBMs, including their origin, the tumor-supportive properties, the secreted cytokines, and the relevant mechanisms. In addition, we tried to interpret the current understandings about the interplay between GBM cancer cells and TAMs. Finally, the translational studies of targeting TAMs were also described.
Glioblastomas are highly lethal brain tumors containing tumor-propagating glioma stem cells (GSCs). The molecular mechanisms underlying the maintenance of the GSC phenotype are not fully defined. Here we demonstrate that the zinc finger and X-linked transcription factor (ZFX) maintains GSC self-renewal and tumorigenic potential by upregulating c-Myc expression. ZFX is differentially expressed in GSCs relative to non-stem glioma cells and neural progenitor cells. Disrupting ZFX by shRNA reduced c-Myc expression and potently inhibited GSC self-renewal and tumor growth. Ectopic expression of c-Myc to its endogenous level rescued the effects caused by ZFX disruption, supporting that ZFX controls GSC properties through c-Myc. Furthermore, ZFX binds to a specific sequence (GGGCCCCG) on the human c-Myc promoter to upregulate c-Myc expression. These data demonstrate that ZFX functions as a critical upstream regulator of c-Myc and plays essential roles in the maintenance of the GSC phenotype. This study also supports that c-Myc is a dominant driver linking self-renewal to malignancy.
Sensitive and selective detection for cancer biomarkers is critical in cancer clinical diagnostics. In this work, we report a new optical microfiber (OMF) biosensor using gold nanoparticles (GNPs) as amplification labels for the detection of alpha-fetoprotein (AFP) in serum samples. By combining the unique optical property of OMFs and the strong optical absorption of GNPs, very high sensitivity and selectivity can be achieved. Critical parameters namely fiber diameter and GNP size were optimized for better performance. The limit of detection (LOD) of this sensor for AFP is 0.2 ng/mL in PBS and 2 ng/mL in bovine serum, which is comparable to conventional assays. The advantages of this biosensor are simple detection scheme, fast response time, and ease of miniaturization, which might make this biosensor a promising platform for clinical cancer diagnosis and prognosis.
We propose a novel structure that can achieve extraordinary optical absorption over the visible spectrum, based on the guided-mode resonance effect. An optical metal grating with moderate thickness and high filling factor can lead to coupling between the quasi-guided-mode and cavity mode. The resonant interaction between the two modes can influence the field distribution, such as the magnetic field near the grating, which results in extraordinary absorption. Absorption efficiency can be optimized up to 99.16%. We also show that the absorption peak can be readily tuned just by varying the subwavelength grating period.
Glioblastomas (GBMs) are highly vascular and lethal brain tumors that display cellular hierarchies containing self-renewing tumorigenic glioma stem cells (GSCs). Because GSCs often reside in perivascular niches and may undergo mesenchymal differentiation, we interrogated GSC potential to generate vascular pericytes. Here, we show that GSCs give rise to pericytes to support vessel function and tumor growth. In vivo cell lineage tracing with constitutive and lineage-specific fluorescent reporters demonstrated that GSCs generate the majority of vascular pericytes. Selective elimination of GSC-derived pericytes disrupts the neovasculature and potently inhibits tumor growth. Analysis of human GBM specimens showed that most pericytes are derived from neoplastic cells. GSCs are recruited toward endothelial cells via the SDF-1/CXCR4 axis and are induced to become pericytes predominantly by transforming growth factor ?. Thus, GSCs contribute to vascular pericytes that may actively remodel perivascular niches. Therapeutic targeting of GSC-derived pericytes may effectively block tumor progression and improve antiangiogenic therapy.
In multiple myeloma (MM), an incurable B cell neoplasm, mutation or deletion of p53 is rarely detected at diagnosis. Using small-molecule inhibitors of MDM2, we provide evidence that miR-192, 194, and 215, which are downregulated in a subset of newly diagnosed MMs, can be transcriptionally activated by p53 and then modulate MDM2 expression. Furthermore, ectopic re-expression of these miRNAs in MM cells increases the therapeutic action of MDM2 inhibitors in vitro and in vivo by enhancing their p53-activating effects. In addition, miR-192 and 215 target the IGF pathway, preventing enhanced migration of plasma cells into bone marrow. The results suggest that these miRNAs are positive regulators of p53 and that their downregulation plays a key role in MM development.
C-terminal Src kinase (Csk) that functions as an essential negative regulator of Src family tyrosine kinases (SFKs) interacts with tyrosine-phosphorylated molecules through its Src homology 2 (SH2) domain, allowing it targeting to the sites of SFKs and concomitantly enhancing its kinase activity. Identification of additional Csk-interacting proteins is expected to reveal potential signaling targets and previously undescribed functions of Csk. In this study, using a direct proteomic approach, we identified 151 novel potential Csk-binding partners, which are associated with a wide range of biological functions. Bioinformatics analysis showed that the majority of identified proteins contain one or several Csk-SH2 domain-binding motifs, indicating a potentially direct interaction with Csk. The interactions of Csk with four proteins (partitioning defective 3 (Par3), DDR1, SYK and protein kinase C iota) were confirmed using biochemical approaches and phosphotyrosine 1127 of Par3 C-terminus was proved to directly bind to Csk-SH2 domain, which was consistent with predictions from in silico analysis. Finally, immunofluorescence experiments revealed co-localization of Csk with Par3 in tight junction (TJ) in a tyrosine phosphorylation-dependent manner and overexpression of Csk, but not its SH2-domain mutant lacking binding to phosphotyrosine, promoted the TJ assembly in Madin-Darby canine kidney cells, implying the involvement of Csk-SH2 domain in regulating cellular TJs. In conclusion, the newly identified potential interacting partners of Csk provided new insights into its functional diversity in regulation of numerous cellular events, in addition to controlling the SFK activity.
Fibroblast growth factor (FGF) receptor substrate 2alpha (FRS2alpha) is the main mediator of signaling in the FGF pathway. Recent studies have shown that mitogen-activated protein kinase (MAPK) phosphorylates serine and threonine residues in FRS2, negatively affecting FGF-induced tyrosine phosphorylation (PY) of FRS2. Several kinds of stimuli can induce serine/threonine phosphorylation (PS/T) of FRS2, indicating that FRS2 may be useful for studying crosstalk between growth factor signaling pathways. Here, we report that FGF-induced PY of FRS2 can be attenuated by EGF co-stimulation in PC12 cells; this inhibitory effect could be completely reversed by U0126, an inhibitor of MEK. We further identified the ERK1/2-binding motif in FRS2 and generated FRS2-3KL, a mutant lacking MAPK binding and PT upon FGF and/or EGF stimulation. Unlike wild-type (WT) FRS2, FGF-induced PY of FRS2-3KL could not be inhibited by EGF co-stimulation, and FRS2-3KL-expressing PC12 cells exhibited more differentiating potential than FRS2-WT-expressing cells in response to FGF treatment. These results suggest that PS/T of FRS2 mediated by the FRS2-MAPK negative regulatory loop may function as a molecular switch integrating negative regulatory signals from other pathways into FGFR-generated signal transduction.
Cdc42, a member of the Rho guanosine triphosphatase (GTPase) family, plays important roles in the regulation of the cytoskeleton, cell proliferation, cell polarity, and cellular transport, but little is known about its specific function in mammalian liver. We investigated the function of Cdc42 in regulating liver regeneration. Using a mouse model with liver-specific knockout of Cdc42 (Cdc42LK), we studied liver regeneration after partial hepatectomy. Histological analysis, immunostaining, and western blot analysis were performed to characterize Cdc42LK livers and to explore the role of Cdc42 in liver regeneration. In control mouse livers, Cdc42 became activated between 3 and 24 hours after partial hepatectomy. Loss of Cdc42 led to a significant delay of liver recovery after partial hepatectomy, which was associated with reduced and delayed DNA synthesis indicated by 5-bromo-2-deoxyuridine staining. Consistent with this, expression of cyclins D1, A, and E was markedly delayed or reduced in Cdc42LK livers during regeneration. As a potential effector of Cdc42, Rac1 activation was dramatically attenuated in Cdc42LK livers after partial hepatectomy, suggesting it is regulated in a Cdc42-dependent manner. Activation of certain proliferative signaling pathways, such as extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p70S6 kinase pathways, was delayed in Cdc42LK livers. In addition, dilated bile canaliculi and excessive lipid accumulation were observed in mutant livers during liver regeneration, which may result from impaired cytoskeletal organization and intracellular trafficking in hepatocytes. Conclusion: Our results revealed important roles of Cdc42 in the regulation of proliferative signaling during liver regeneration.
The oncogenic roles contributed by the Akt/PKB kinase family remain controversial and presumably depend on cell context, but are perceived to be modulated by an interplay and net balance between various isoforms. This study is intended to decipher whether distinct Akt kinase isoforms exert either redundant or unique functions in regulating neoplastic features of breast cancer cells, including epithelial-mesenchymal transition (EMT), cell motility, and stem/progenitor cell expansion.
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