Oligo-benzamide-based peptide mimicking tools for modulating biology.

The oligo-benzamide scaffold is a rigid organic framework that can hold 2-3 functional groups as O-alkyl substituents on its benzamide units, mirroring their natural arrangement in an α-helix. Oligo-benzamides demonstrated outstanding α-helix mimicry and can be readily synthesized by following high yielding and iterative reaction steps in both solution-phase and solid-phase. A number of oligo-benzamides have been designed to emulate α-helical peptide segments in biologically active proteins and showed strong protein binding, in turn effectively disrupting protein-protein interactions in vitro and in vivo. In this chapter, the design of oligo-benzamides for mimicking α-helices, efficient synthetic routes for producing them, and their biomedical studies showing remarkable potency in inhibiting protein functions are discussed.

Steric Effects on the Photovoltaic Performance of Panchromatic Ruthenium Sensitizers for Dye-Sensitized Solar Cells.

Three new heteroleptic Ru complexes, CYC-B22, CYC-B23C, and CYC-B23T, were prepared as sensitizers for coadsorbent-free, panchromatic, and efficient dye-sensitized solar cells. They are simultaneously functionalized with highly conjugated anchoring and ancillary ligands to explore the electronic and steric effects on their photovoltaic characteristics. The coadsorbent-free device based on CYC-B22 achieved the best power conversion efficiency (PCE) of 8.63% and a panchromatic response extending to 850 nm. The two stereoisomers, CYC-B23C and CYC-B23T coordinated with an unsymmetrical anchoring ligand, display similar absorption properties and the same driving forces for electron injection as well as dye regeneration. Nevertheless, the devices show not only the remarkably distinct PCE (6.64% vs 8.38%) but also discernible stability. The molecular simulation for the two stereoisomers adsorbed on TiO2 clarifies the distinguishable distances (16.9 Å vs 19.0 Å) between the sulfur atoms in the NCS ligands and the surface of the TiO2, dominating the charge recombination dynamics and iodine binding and therefore the PCE and stability of the devices. This study on the steric effects caused by the highly conjugated and unsymmetrical anchoring ligand on the adsorption geometry and photovoltaic performance of the dyes paves a new way for advancing the molecular design of polypyridyl metal complex sensitizers.

Novel LIPA-Targeted Therapy for Treating Ovarian Cancer.

Ovarian cancer (OCa) is the most lethal form of gynecologic cancer, and the tumor heterogeneities at the molecular, cellular, and tissue levels fuel tumor resistance to standard therapies and pose a substantial clinical challenge. Here, we tested the hypothesis that the heightened basal endoplasmic reticulum stress (ERS) observed in OCa represents an exploitable vulnerability and may overcome tumor heterogeneity. Our recent studies identified LIPA as a novel target to induce ERS in cancer cells using the small molecule ERX-41. However, the role of LIPA and theutility of ERX-41 to treat OCa remain unknown. Expression analysis using the TNMplot web tool, TCGA data sets, and immunohistochemistry analysis using a tumor tissue array showed that LIPA is highly expressed in OCa tissues, compared to normal tissues. ERX-41 treatment significantly reduced the cell viability and colony formation ability and promoted the apoptosis of OCa cells. Mechanistic studies revealed a robust and consistent induction of ERS markers, including CHOP, elF2α, PERK, and ATF4, upon ERX-41 treatment. In xenograft and PDX studies, ERX-41 treatment resulted in a significant reduction in tumor growth. Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of ERS induction, which could be exploited to treat heterogeneity in OCa.

Enhancing Near-Infrared Absorption in Terpyridyl Ru/Os Complexes with Ancillary Ligands to Activate Spin-Forbidden Transitions in Dye-Sensitized Solar Cells: A TDDFT Investigation.

Dye sensitizers with wideband absorption covering the near-IR region have long been of interest because they potentially harvest a wide range of solar energies essential to promote photocurrent power conversion efficiencies. In this study, we used time-dependent density functional theory with spin-orbit (SO) interactions to theoretically explore the long-wavelength absorptions and spin-forbidden triplet transitions activated by SO interactions for terpyridyl ruthenium/osmium complex dyes. These dyes feature a Ru(II) sensitizer coordinated with a phosphine ligand and are exemplified by DX1, denoted as [trans-dichloro-(phenyldimethoxyphosphine)(2,2';6',2″-terpyridyl-4,4',4″-tricarboxylic)Ru]. We found that ancillary ligands significantly affected the longest wavelength spin-allowed absorption, with NCS- ligands yielding longer wavelength S1 transitions than halides. High atomic number halide ligands caused blue shifts in the S1 transition. Os complexes consistently exhibited longer wavelength S1 transitions than Ru complexes with identical ligands. In Ru/Os complexes, ancillary ligands with higher atomic numbers have a more pronounced effect in activating spin-forbidden triplet transitions through spin-orbit coupling (SOC) than those with lower atomic numbers. The absorption wavelength of the SOC-activated transition primarily depended on the energy of lower lying triplet states. Some complexes exhibited T1 states activated by SOC, leading to longer wavelength absorption than that of SOC-activated T2 states. Our study revealed the significance of ancillary ligands and SOC interactions in Ru/Os complexes, offering insights for optimizing materials with enhanced long-wavelength absorption properties, particularly in the near-IR range, for photovoltaic and optoelectronic applications.

Behavioural responses of zebrafish with sound stimuli in microfluidics.

Neuronal activities of the human brain responsible for cognitive features have been theorized through several animal models that exhibited various complementary spatial learning modes by generating a flexible repertoire of behavioral strategies. However, for such studies associated with a neurodegenerative disease, which can be further manipulated to provide therapeutic strategies, the animal models employed in their developmental stages have been preferred over the adult ones. This pilot work was incepted to underscore the spatial memory capabilities that strengthened the intricate mechanism of memory acquisition potential in one of the low-order evolutionarily conserved species, such as zebrafish larvae. Initially, a reliable and more easily reproducible microfluidic platform integrating simple and intricate paths was designed to learn and test the spatial information in zebrafish larvae of 4-6 d.p.f. under non-invasive acoustic stimuli. Further, to acquire spatial information as the representation of spatial memory formation in zebrafish larvae, the acoustic startle responses were evaluated by quantifying various dynamic behaviors under distinct operating parameters. After significant conditioning sessions, the spatial memory was tested by employing variable 'freezing'. By the end of the 30 min-long test session, 6 d.p.f. larvae were found to exhibit the highest value of freezing of approximately 43% and 20% in the short and long paths, respectively. Even though a substantial rate of memory loss was observed, it can be envisaged to serve several behavioral strategies that process the dynamic cognitive memory among distinct spatiotemporal environments. Further, the proposed behavioral paradigm had the advantage of being more adaptable and reliably replicable by other researchers. As a consequence, different hypotheses can be readily tested to generate more reproducible findings towards distinct neurobehavioral characteristics. Therefore, the proposed paradigm for the consolidation of spatial memory based on the non-invasive spatial avoidance strategies could provide an enduring framework of reference for behavioral studies using zebrafish larvae.

The Association Between Dextromethorphan Use and the Risk of Dementia.

Dementia is one of neurodegenerative disease without preventive medicine currently. Dextromethorphan (DXM) has been reported to reduce neuronal damage and neurodegeneration in animal and human models. The effect of DXM on the dementia has not been fully examined. We examined the medical records over 40 years old in Taiwan's National Health Insurance Research Database between 2000 and 2015 to establish matched cohorts. We used a Cox regression hazard model to identify risk factors of dementia during 16 years of follow-up, and the results indicate that a significantly lower percentage of subjects with DXM use (P < .001) developed dementia compared with those without DXM use (11.38%, 4541/39 895 vs 18.66%, 29 785/159 580). After adjustment for age and other variables [adjusted hazard ratio: .567 (95% confidence interval: .413-.678, P < .001)], this study also demonstrated that DXM use appeared to reduce the risk of developing dementia. DXM use may potentially provide a protective effect against dementia.

Microfluidic Applications of Artificial Cilia: Recent Progress, Demonstration, and Future Perspectives.

Artificial cilia-based microfluidics is a promising alternative in lab-on-a-chip applications which provides an efficient way to manipulate fluid flow in a microfluidic environment with high precision. Additionally, it can induce favorable local flows toward practical biomedical applications. The endowment of artificial cilia with their anatomy and capabilities such as mixing, pumping, transporting, and sensing lead to advance next-generation applications including precision medicine, digital nanofluidics, and lab-on-chip systems. This review summarizes the importance and significance of the artificial cilia, delineates the recent progress in artificial cilia-based microfluidics toward microfluidic application, and provides future perspectives. The presented knowledge and insights are envisaged to pave the way for innovative advances for the research communities in miniaturization.

An aquatic microrobot for microscale flow manipulation.

Microrobots have been developed and extensively employed for performing the variety tasks with various applications. However, the intricate fabrication and actuation processes employed for microrobots further restrict their multitudinous applicability as well as the controllability in high accuracy. As an alternative, in this work an aquatic microrobot was developed using a distinctive concept of the building block technique where the microrobot was built based on the block to block design. An in-house electromagnetic system as well as the control algorithm were developed to achieve the precise real-time dynamics of the microrobot for extensive applications. In addition, pivotal control parameters of the microrobot including the actuating waveforms together with the operational parameters were verified and discussed in conjunction with the magnetic intensity simulation. A mixing task was performed with high efficiency based on the trajectory planning and rotation control of the microrobot to demonstrate its capability in flow manipulation which can be advantageous for microreactor applications down the load. Aside from it, a dissolution test was further conducted to provide an on-demand flow agitation function of the microrobot for the next level of lab chip applications. The presented work with detail dynamic analysis is envisaged to provide a new look of microrobot control and functions from the engineering perspective with profoundly potential applications.

Shape-programmable artificial cilia for microfluidics.

The artificial ciliary motion has been known not to be hydrodynamically optimal, limiting their associated applications in the microscale flow domain. One of the major hurdles of contemporary artificial cilia is its structural rigidity, which restricts their flexibility. To address this issue, this work proposed a shape-programmable artificial cilia design with distinctive polydimethylsiloxane (PDMS) and magnetic segments distributed throughout the structure, which provided precise control for time-spatial modulation of the whole artificial cilia structure under external magnetic actuation. For the fabrication of the proposed multi-segment artificial cilia, a facile microfabrication process with stepwise mold blocking followed by the PDMS and magnetic composite casting was adopted. The hydrodynamic analysis further elucidated that the proposed artificial cilia beating induced significant flow disturbance within the flow field, and the associated application was demonstrated through an efficient mixing operation.

Investigation of 3.3 kV 4H-SiC DC-FSJ MOSFET Structures.

This research proposes a novel 4H-SiC power device structure-different concentration floating superjunction MOSFET (DC-FSJ MOSFET). Through simulation via Synopsys Technology Computer Aided Design (TCAD) software, compared with the structural and static characteristics of the traditional vertical MOSFET, DC-FSJ MOSFET has a higher breakdown voltage (BV) and lower forward specific on-resistance (Ron,sp). The DC-FSJ MOSFET is formed by multiple epitaxial technology to create a floating P-type structure in the epitaxial layer. Then, a current spreading layer (CSL) is added to reduce the Ron,sp. The floating P-type structure depth, epitaxial layer concentration and thickness are optimized in this research. This structure can not only achieve a breakdown voltage over 3300 V, but also reduce Ron,sp. Under the same conditions, the Baliga Figure of Merit (BFOM) of DC-FSJ MOSFET increases by 27% compared with the traditional vertical MOSFET. Ron,sp is 25% less than that of the traditional vertical MOSFET.

The evaluation of zebrafish cardiovascular and behavioral functions through microfluidics.

This study proposed a new experimental approach for the vascular and phenotype evaluation of the non-anesthetized zebrafish with representative imaging orientations for heart, pectoral fin beating, and vasculature views by means of the designed microfluidic device through inducing the optomotor response and hydrodynamic pressure control. In order to provide the visual cues for better positioning of zebrafish, computer-animated moving grids were generated by an in-house control interface which was powered by the larval optomotor response, in conjunction with the pressure suction control. The presented platform provided a comprehensive evaluation of internal circulation and the linked external behaviors of zebrafish in response to the cardiovascular parameter changes. The insights from these imaging sections was extended to identify the linkage between the cardiac parameters and behavioral endpoints. In addition, selected chemicals such as ethanol and caffeine were employed for the treatment of zebrafish. The obtained findings can be applicable for future investigation in behavioral drug screening serving as the forefront in psychopharmacological and cognition research.

Enhancing immunogenicity of HPV16 E7 DNA vaccine by conjugating codon-optimized GM-CSF to HPV16 E7 DNA.

OBJECTIVE: To generate immunity against human papillomavirus (HPV), the use of a recombinant DNA vaccine to carry an appropriate target gene is a promising and cost-effective approach. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent immunomodulatory cytokine that enhances the efficacy of vaccines by promoting the development and prolongation of humoral and cellular immunity. In this study, we linked codon-optimized GM-CSF (cGM-CSF) to the HPV16 E7 sequence as fused protein and evaluated the immunogenic potential of this DNA vaccine. MATERIALS AND METHODS: We have demonstrated that cGM-CSF enhanced immunity against tumor challenges by generating and promoting the proliferation of HPV16 E7-specific CD8+ T cells, which secrete IFN-γ in the murine model. In this study, we aimed to evaluate the immunogenic potential of DNA vaccine that constructed by linking codon-optimized GM-CSF to HPV16 E7 sequence in the animal model. We study the half-life of RNA decay and cellular location of HPV16 E7 by Q-PCR and Western blot. We also assess immune response in the animal model by flow cytometry and ELISA. RESULTS: The cGM-CSF-E7 sequence increased and extended the expression of E7 mRNA, in comparison with the E7 sequence alone. Mice vaccinated with the cGM-CSF-E7 DNA vaccine exhibited a slower rate of tumor growth than those vaccinated with the unconjugated E7 DNA vaccine. We also found that the CD4 and CD8+ T cells from these mice showed strong secretion of IFN-γ. CONCLUSION: Through in vivo antibody depletion experiments, we demonstrated that both CD4+ and CD8+ T cells play an important role in the suppression of tumor growth.

A non-invasive acoustic-trapping of zebrafish microfluidics.

Zebrafish is an emerging alternative model in behavioral and neurological studies for pharmaceutical applications. However, little is known regarding the effects of noise exposure on laboratory-grown zebrafish. Accordingly, this study commenced by exposing zebrafish embryos to loud background noise (≥200 Hz, 80 ± 10 dB) for five days in a microfluidic environment. The noise exposure was found to affect the larvae hatching rate, larvae length, and swimming performance. A microfluidic platform was then developed for the sorting/trapping of hatched zebrafish larvae using a non-invasive method based on light cues and acoustic actuation. The experimental results showed that the proposed method enabled zebrafish larvae to be transported and sorted into specific chambers of the microchannel network in the desired time frame. The proposed non-invasive trapping method thus has potentially profound applications in drug screening.

Comprehensive Hydrodynamic Investigation of Zebrafish Tail Beats in a Microfluidic Device with a Shape Memory Alloy.

The zebrafish is acknowledged as a reliable species of choices for biomechanical-related investigations. The definite quantification of the hydrodynamic flow physics caused by behavioral patterns, particularly in the zebrafish tail beat, is critical for a comprehensive understanding of food toxicity in this species, and it can be further interpreted for possible human responses. The zebrafish's body size and swimming speed place it in the intermediate flow regime, where both viscous and inertial forces play significant roles in the fluid-structure interaction. This pilot work highlighted the design and development of a novel microfluidic device coupled with a shape memory alloy (SMA) actuator to immobilize the zebrafish within the observation region for hydrodynamic quantification of the tail-beating behavioral responses, which may be induced by the overdose of food additive exposure. This study significantly examined behavioral patterns of the zebrafish in early developmental stages, which, in turn, generated vortex circulation. The presented findings on the behavioral responses of the zebrafish through the hydrodynamic analysis provided a golden protocol to assess the zebrafish as an animal model for new drug discovery and development.

Edible additive effects on zebrafish cardiovascular functionality with hydrodynamic assessment.

Food coloring is often used as a coloring agent in foods, medicines and cosmetics, and it was reported to have certain carcinogenic and mutagenic effects in living organisms. Investigation of physiological parameters using zebrafish is a promising methodology to understand disease biology and drug toxicity for various drug discovery on humans. Zebrafish (Danio rerio) is a well-acknowledged model organism with combining assets such as body transparency, small size, low cost of cultivation, and high genetic homology with humans and is used as a specimen tool for the in-vivo throughput screening approach. In addition, recent advances in microfluidics show a promising alternative for zebrafish manipulation in terms of drug administration and extensive imaging capability. This pilot work highlighted the design and development of a microfluidic detection platform for zebrafish larvae through investigating the effects of food coloring on cardiovascular functionality and pectoral fin swing ability. The zebrafish embryos were exposed to the Cochineal Red and Brilliant Blue FCF pigment solution in a concentration of (0.02‰, 0.2‰) cultured in the laboratory from the embryo stage to hatching and development until 9 days post fertilization (d.p.f.). In addition, zebrafish swimming behaviors in terms of pectoral fin beating towards the toxicity screening were further studied by visualizing the induced flow field. It was evidenced that Cochineal Red pigment at a concentration of 0.2‰ not only significantly affected the zebrafish pectoral fin swing behavior, but also significantly increased the heart rate of juvenile fish. The higher concentration of Brilliant Blue FCF pigment (0.2%) increased heart rate during early embryonic stages of zebrafish. However, zebrafish exposed to food coloring did not show any significant changes in cardiac output. The applications of this proposed platform can be further extended towards observing the neurobiological/hydrodynamic behaviors of zebrafish larvae for practical applications in drug tests.

Extending Absorption Edge through the Hybrid Resonator-Based Absorber with Wideband and Near-Perfect Absorption in Visible Region.

Metamaterial absorber with the unexpected capability for harvesting electromagnetic energy has been regarded as a potential route for various applications, including chemical/biological sensing, cloaking and photovoltaic applications. In this study, we presented the simple absorber design made with Al/SiO2/Al sandwich structures through the involvement of hybrid dual-resonators that could allow the wideband light absorption covered from 450 nm to 600 nm with average absorptivity above 95%. Examinations of excited electric field, magnetic field and total magnitude of electric field in three-dimensional space at resonances were performed to clarify the origin of resonant behaviors. In addition, an equivalent inductance-capacitance circuit model was proposed that could qualitatively explore the geometry-dependent absorption characteristics by modulating the constitutive parameters of hybrid resonators. As a result, the designed light absorber might enable to be practically applied for various optical-management and photovoltaic applications, and even offered the tunability for other desired frequency regions.

Microfluidic Transportation Control of Larval Zebrafish through Optomotor Regulations under a Pressure-Driven Flow.

To perform zebrafish larvae-related experiments within a microfluidic environment, the larvae need to be anesthetized and subsequently transported into respective test sections through mechanical or manual means. However, anesthetization tends to affect larval sensory perceptions, hindering their natural behaviors. Taking into account that juvenile larvae move naturally within their environment by accessing visual as well as hydromechanical cues, this work proposes an experimental framework to transport nonanesthetized larvae within a microfluidic environment by harmonically tuning both of the aforementioned cues. To provide visual cues, computer-animated moving gratings were provided through an in-house-developed control interface that drove the larval optomotor response. In the meantime, to provide hydromechanical cues, the flow rate was tuned using a syringe pump that affected the zebrafish larvae's lateral line movement. The results obtained (corresponding to different test conditions) suggest that the magnitude of both modalities plays a crucial role in larval transportation and orientation control. For instance, with a flow rate tuning of 0.1 mL/min along with grating parameters of 1 Hz temporal frequency, the average transportation time for larvae that were 5 days postfertilization was recorded at 1.29 ± 0.49 s, which was approximately three times faster than the transportation time required only in the presence of hydromechanical cues.

Microfluidic retention of progressively motile zebrafish sperms.

Genetic manipulation of zebrafish results in thousands of mutant strains and to efficiently preserve them for future use, zebrafish sperms have been cryopreserved in various cryopreservation centers. However, cryopreservation protocols are known to alter genetic entities. Therefore, there is an urgent need for an efficient method that can select morphologically superior and progressively motile zebrafish sperms after their activation for in vitro fertilization success. However, unlike those of other mammalian species, fish sperms do not take any physical or chemical cues to travel towards the egg. Their inertness towards any external cues makes the control of their orientation in a microfluidic environment difficult. In this aspect, a new microfluidic concept was demonstrated where PDMS baffles were inserted in the sidewalls to form microscale confinement creating a flow stagnation zone towards sperm retention. Two distinct microfluidic device designs were selected to evidence the improvement in sperm retention through the unique hydrodynamic feature provided by the microchannel design. Under similar flow conditions, 44% improvement was noticed for the device with a modified baffle design in terms of sperm retrieving efficiency. It was further noticed that with a flow tuning of 0.7 µL min-1, 80% of the total sperms swimming into the retention zones was retained within a specific time window. The present work further explains the significance of the hydrodynamic dependency of zebrafish sperm kinematics that paves the way for highly efficient spermatozoan manipulation.

Thrust and Hydrodynamic Efficiency of the Bundled Flagella.

The motility mechanism of prokaryotic organisms has inspired many untethered microswimmers that could potentially perform minimally invasive medical procedures in stagnant fluid regions inside the human body. Some of these microswimmers are inspired by bacteria with single or multiple helical flagella to propel efficiently and fast. For multiple flagella configurations, the direct measurement of thrust and hydrodynamic propulsion efficiency has been challenging due to the ambiguous mechanical coupling between the flow field and mechanical power input. To address this challenge and to compare alternative micropropulsion designs, a methodology based on volumetric velocity field acquisition is developed to acquire the key propulsive performance parameters from scaled-up swimmer prototypes. A digital particle image velocimetry (PIV) analysis protocol was implemented and experiments were conducted with the aid of computational fluid dynamics (CFD). First, this methodology was validated using a rotating single-flagellum similitude model. In addition to the standard PIV error assessment, validation studies included 2D vs. 3D PIV, axial vs. lateral PIV and simultaneously acquired direct thrust force measurement comparisons. Compatible with typical micropropulsion flow regimes, experiments were conducted both for very low and higher Reynolds (Re) number regimes (up to a Re number = 0.01) than that are reported in the literature. Finally, multiple flagella bundling configurations at 0°, 90° and 180° helical phase-shift angles were studied using scaled-up multiple concentric flagella thrust elements. Thrust generation was found to be maximal for the in-phase (0°) bundling configuration but with ~50% lower hydrodynamic efficiency than the single flagellum. The proposed measurement protocol and static thrust test-bench can be used for bio-inspired microscale propulsion methods, where direct thrust and efficiency measurement are required.

Suppression of tumor growth via IGFBP3 depletion as a potential treatment in glioma.

OBJECTIVE: Despite intensive medical treatment, patients with glioblastoma (grade IV glioma [GBM]) have a low 5-year survival rate of 5.5%. In this study, the authors tried to improve currently used therapies by identification of a therapeutic target, IGFBP3, for glioma treatment. METHODS: IGFBP3 RNA expression in 135 patients newly diagnosed with glioma was correlated with clinicopathological factors. Immunohistochemical analysis was performed to determine IGFBP3 protein expression in glioma specimens. The effect of IGFBP3 depletion on cell proliferation was examined using IGFBP3 knockdown glioma cells. Intracranial infusion of IGFBP3 siRNAs was performed to evaluate the effect of IGFBP3 depletion in mouse intracranial xenograft models. RESULTS: We demonstrated higher IGFBP3 expression in GBM than in tumor margin and grade II glioma. IGFBP3 expression was not only positively correlated with tumor grades but also associated with tumor histology and IDH1/2 mutation status. Additionally, higher IGFBP3 expression predicted shorter overall survival in glioma and GBM proneural subgroup patients. In vitro cell culture studies suggested IGFBP3 knockdown suppressed cell proliferation and induced cell cycle G2/M arrest as well as apoptosis in glioma cells. Also, accumulation of DNA double-strand breaks and γH2AX was observed in IGFBP3 knockdown cells. IGFBP3 knockdown delayed in vivo tumor growth in mouse subcutaneous xenograft models. Furthermore, convection-enhanced delivery of IGFBP3 siRNA to mouse brain suppressed intracranial tumor growth and prolonged survival of tumor-bearing mice. CONCLUSIONS: Our findings suggest IGFBP3 predicts poor outcome of glioma patients and is a potential therapeutic target for which depletion of its expression suppresses tumor growth through inducing apoptosis and accumulation of DNA damage in glioma cells.